Cancer

Coding Dimension ID: 
280
Coding Dimension path name: 
Cancer
Funding Type: 
Early Translational IV
Grant Number: 
TR4-06867
Investigator: 
Name: 
Type: 
Co-PI
ICOC Funds Committed: 
$4 075 668
Disease Focus: 
Prostate Cancer
Cancer
Stem Cell Use: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 
Metastatic disease and the castration resistance remain tremendous challenges in the treatment of prostate cancer. New targeted treatments, such as the ant-testosterone medication enzalutamide, have improved the survival of men with advanced disease, but a majority develops treatment resistance. The field of cancer stem cells hypothesizes that treatment resistance emerges because stem cells are inherently resistant to our current therapies and eventually repopulate tumors. One mechanism by which cancer stem cells resist therapy is through acquisition of an epithelial to mesenchymal transition (EMT), a phenomenon of normal development used by cancers to survive and metastasize. Our laboratory has shown that prostate cancers undergo an EMT that leads to invasion, metastasis and treatment resistance. N-cadherin, a critical regulator of EMT, is expressed in most castration resistant prostate cancers (CRPC) and is sufficient to promote treatment resistance. We therefore developed antibodies against N-cadherin, which are able to inhibit growth, metastasis and progression of prostate cancers in vivo. The goal of this translational application is to move this promising treatment from the laboratory to the clinic by making the antibody human, making it bind more strongly, and then testing it for toxicity, behavior and anti-tumor activity. At the completion of this project, we will be poised to manufacture this lead molecule and move expeditiously to Phase I clinical studies.
Statement of Benefit to California: 
Prostate cancer is the second leading cause of cancer-related death in Californian men. With an aging population, this problem is expected to continue to grow despite recent advances in treatment. The goal of this application is to develop a novel antibody targeting a cancer stem cell target in hormone and treatment refractory prostate cancer. The benefit to the California, if successful, will be the development of a novel therapy against this common disease.
Progress Report: 
  • Metastatic disease and the castration resistance remain tremendous challenges in the treatment of prostate cancer. New targeted treatments, such as the anti-testosterone medication enzalutamide, have improved the survival of men with advanced disease, but a majority develops treatment resistance. The field of cancer stem cells hypothesizes that treatment resistance emerges because stem cells are inherently resistant to our current therapies and eventually repopulate tumors. One mechanism by which cancer stem cells resist therapy is through acquisition of an epithelial to mesenchymal transition (EMT), a phenomenon of normal development used by cancers to survive and metastasize. Our laboratory has shown that prostate cancers undergo an EMT that leads to invasion, metastasis and treatment resistance. N-cadherin, a critical regulator of EMT, is expressed in most castration resistant prostate cancers (CRPC) and is sufficient to promote treatment resistance. We therefore developed antibodies against N-cadherin, which are able to inhibit growth, metastasis and progression of prostate cancers in vivo. The goal of this translational application is to move this promising treatment from the laboratory to the clinic by making the antibody human, making it bind more strongly, and then testing it for toxicity, behavior and anti-tumor activity. At the completion of this project, we will be poised to manufacture this lead molecule and move expeditiously to Phase I clinical studies.
  • At this juncture in the project, we have made our two original lead antibodies into human ones that would not elicit an immune response in patients. We have begun to test these “humanized” antibodies and they appear to retain the properties of the mouse ones from which they were derived. We have also generated additional candidate antibody drugs through screening of a library containing millions of candidate antibodies. We have narrowed these candidates down to approximately 9, and are continuing to work to prioritize these based on activity. Finally, we have begun the process of maturing these lead candidates to bind more tightly to N-cadherin, the target, hypothesizing that this will further improve the efficacy of these drugs moving forward. Over the coming months, we will finalize selection of 2-3 lead antibodies and begin testing them in animal experiments as the next step toward realizing the goal of testing them in patients.
Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06510
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$2 800 536
Disease Focus: 
Neurological Disorders
Brain Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Chemotherapy for cancer is often life saving, but it also causes a debilitating syndrome of impaired cognition characterized by deficits in attention, concentration, information processing speed, multitasking and memory. As a result, many cancer survivors find themselves unable to return to work or function in their lives as they had before their cancer therapy. These cognitive deficits, colloquially known as "chemobrain" or "chemofog," are long-lasting and sometimes irreversible. For example, breast cancer survivors treated with chemotherapy suffer from cognitive disability even 20 years later. These cognitive problems occur because chemotherapy damages the neural stem and precursor cells necessary for the health of the brain's infrastructure, called white matter. We have discovered a powerful way to recruit the stem/precursor cells required for white matter repair that depends on an interaction between the electrical cells of the brain, neurons, and these white matter stem/precursor cells. In this project, we will determine the key molecules responsible for the regenerative influence of neurons on these white matter stem cells and will develop that molecule (or molecules) into a drug to treat chemotherapy-induced cognitive dysfunction. If successful, this will result in the first effective treatment for a disease that affects at least a million cancer survivors in California.
Statement of Benefit to California: 
Approximately 100,000 Californians are diagnosed with cancer each year, and the majority of these people require chemotherapy. While cancer chemotherapy is often life saving, it also causes a debilitating neurocognitive syndrome characterized by impaired attention, concentration, information processing speed, multitasking and memory. As a result, many cancer survivors find themselves unable to return to work or function in their lives as they had before their cancer therapy. These cognitive deficits, colloquially known as "chemobrain" or "chemofog" are long-lasting; for example, cognitive deficits have been demonstrated in breast cancer survivors treated with chemotherapy even 20 years later. With increasing cancer survival rates, the number of people living with cognitive disability from chemotherapy is growing and includes well over a million Californians. Presently, there is no known therapy for chemotherapy-induced cognitive decline, and physicians can only offer symptomatic treatment with medications such as psychostimulants. The underlying cause of "chemobrain" is damage to neural stem and precursor cell populations. The proposed project may result in an effective regenerative strategy to restore damaged neural precursor cell populations and ameliorate or cure the cognitive syndrome caused by chemotherapy. The benefit to California in terms of improved quality of life for cancer survivors and restored occupational productivity would be immeasurable.
Progress Report: 
  • Cancer chemotherapy can be lifesaving but frequently results in long-term cognitive deficits. This project seeks to establish a regenerative strategy for chemotherapy-induced cognitive dysfunction by harnessing the potential of the interactions between active neurons and glial precursor cells that promote myelin plasticity in the healthy brain. In the first year of this award, we have made on-track progress towards establishing a working experimental model system of chemotherapy-induced neurotoxicity that faithfully models the human disease both in terms of the cellular damage as well as functional deficits in cognition. We have also been able to identify several therapeutic candidate molecules that we will be studying in the coming years of the project to ascertain which of these candidates are sufficient to promote OPC population repletion and neuro-regeneration after chemotherapy exposure.
Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06479
Investigator: 
ICOC Funds Committed: 
$3 084 000
Disease Focus: 
Blood Disorders
Blood Cancer
Cancer
Stem Cell Use: 
Directly Reprogrammed Cell
Cell Line Generation: 
Directly Reprogrammed Cell
oldStatus: 
Active
Public Abstract: 
The current roadblocks to hematopoietic stem cell (HSC) therapies include the rarity of matched donors for bone marrow transplant, engraftment failures, common shortages of donated blood, and the inability to expand HSCs ex vivo in large numbers. These major obstacles would cease to exist if an extensive, bankable, inexhaustible, and patient-matched supply of blood were available. The recent validation of hemogenic endothelium (blood vessel cells lining the vessel wall give rise to blood stem cells) has introduced new possibilities in hematopoietic stem cell therapy. As the phenomenon of hemogenic endothelium only occurs during embryonic development, we aim to understand the requirements for the process and to re-engineer mature human endothelium (blood vessels) into once again producing blood stem cells (HSCs). The approach of re-engineering tissue specific de-differentiation will accelerate the pace of discovery and translation to human disease. Engineering endothelium into large-scale hematopoietic factories can provide substantial numbers of pure hematopoietic stem cells for clinical use. Higher numbers of cells, and the ability to grow cells from matched donors (or the patients themselves) will increase engraftment and decrease rejection of bone marrow transplantation. In addition, the ability to program mature lineage restricted cells into more primitive versions of the same cell lineage will capitalize on cell renewal properties while minimizing malignancy risk.
Statement of Benefit to California: 
Bone marrow transplantation saves the lives of millions with leukemia and other diseases including genetic or immunologic blood disorders. California has over 15 centers serving the population for bone marrow transplantation. While bone marrow transplantation can be seen as a standard to which all stem cell therapies should aspire, there still remains the difficulty of finding matched donors, complications such as graft versus host disease, and the recurrence of malignancy. While cord blood has provided another donor source of stem cells and improved engraftment, it still requires pooling from multiple donors for sufficient cell numbers to be transplanted, which may increase transplant risk. By understanding how to reprogram blood vessels (such as those in the umbilical cord) for production of blood stem cells (as it once did during human development), it could eventually be possible to bank umbilical cord vessels to provide a patient matched reproducible supply of pure blood stem cells for the entire life of the patient. Higher numbers of cells, and the ability to grow cells from matched donors (or the patients themselves) will increase engraftment and decrease rejection of bone marrow transplantation. In addition, the proposed work will introduce a new approach to engineering human cells. The ability to turn back the clock to near mature cell specific stages without going all the way back to early embryonic stem cell stages will reduce the risk of malignancy.
Progress Report: 
  • We aim to understand how blood stem cells develop from blood vessels during development. We are also interested in learning whether the blood-making program can be turned back on in blood vessel cells for blood production outside the human body. During the past year we have been able to extract and culture blood vessel cells that once had blood making capacity. We have also started experiments that will help uncover the regulation of the blood making program. In addition, we have developed tools to help the process of understanding whether iPS technology can "turn back time" in mature blood vessels and turn on the blood making program.
Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06036
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 244 455
Disease Focus: 
Blood Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 
Leukemias are cancers of the blood cells that result from corruption of the normal controls that regulate blood-forming stem cells. They are serious causes of illness and death, and are particularly devastating in children and the elderly. Despite substantial advances in treatment of leukemia, a significant proportion of cases are unresponsive to current therapy. Since more aggressive chemotherapy regimens provide only marginal improvements in therapeutic efficacy, we have reached a point of diminishing returns using currently available drugs. Thus, there is an urgent need for more targeted, less toxic, and more effective treatments. To this end, our studies focus on defining the defects that corrupt the normal growth controls on blood stem cells. The proposed studies build on our discovery of a key enzyme with an unexpected causative role in leukemia. We propose to further characterize its function using various proteomic approaches, and employ a cross-species comparative approach to identify additional pathways unique to cancer stem cell function. The proposed characterization of crucial growth controls that go awry in blood stem cells to cause leukemia will identify new drug targets for more effective and less toxic treatments against these devastating, life-threatening diseases.
Statement of Benefit to California: 
Leukemias are cancers of the blood cells that cause serious illness and death in children and adults. They result from corruption of the normal controls that regulate blood-forming stem cells. Despite many attempts to improve treatments with new drug combinations, this approach has reached a point of diminishing returns since intensified chemotherapies contribute only marginal improvement in outcome and are associated with increasing toxicity. The proposed characterization of crucial growth controls that go awry in blood stem cells to cause leukemia will identify new drug targets for more effective and less toxic treatments against these devastating, life-threatening diseases.
Progress Report: 
  • Leukemias are cancers of the blood cells that cause serious illness and death in children and adults. Even patients who are successfully cured of their disease often suffer from long-term deleterious health effects of their curative treatment. Thus, there is a need for more targeted, less toxic, and more effective treatments. Our studies focus on the defects and mechanisms that induce leukemia by disrupting the normal growth controls that regulate blood-forming stem cells. Using a comparative genomics approach we have identified genes that are differentially expressed in leukemia stem cells. These genes have been the focus of our studies to establish better biomarkers and treatment targets. One candidate gene codes for an enzyme with a previously unknown, non-canonical causal role in a specific genetic subtype of leukemia caused by abnormalities of the MLL oncogene. To characterize its molecular contributions, we are identifying and characterizing protein partners that may assist and interact with the enzyme in its oncogenic role. Candidate interaction partners have been identified using proteomic techniques, and are being investigated for their possible mechanistic roles in leukemia stem cell functions. Another promising candidate that we identified in the comparative gene expression approach encodes a cell surface protein that is preferentially expressed on leukemia stem cells. We have exploited this cell surface protein as a marker to isolate the rare population of cells in human leukemias with stem cell properties. This technical approach has resulted in the isolation of leukemia stem cell populations that are more highly enriched than those obtained using previous techniques. The highly enriched sub-population of leukemia stem cells has been used for comparative gene expression profiling to define a dataset of genes that are differentially expressed between highly matched populations of leukemia cells that are enriched or depleted of leukemia stem cells. Bioinformatics analysis of the dataset has further suggested specific cellular processes and transcriptional regulatory factors that distinguish human leukemia stem cells caused by abnormalities of the MLL oncogene. These newly identified factors will be studied using in vitro and in vivo assays for their specific contributions to leukemia stem cell function and leukemia pathogenesis. Continued characterization of crucial growth controls that go awry in blood stem cells to cause leukemia will identify new drug targets for more effective and less toxic treatments against these devastating, life-threatening diseases.
  • Leukemias are cancers of the blood cells that cause serious illness and death in children and adults. Even patients who are successfully cured of their disease often suffer from long-term adverse health effects of their curative treatment. Thus, there is a need for more targeted, less toxic, and more effective treatments. Our studies focus on the defects and mechanisms that induce leukemia by disrupting the normal growth controls that regulate blood-forming stem cells. Using a comparative genomics approach we have identified genes that are differentially expressed in leukemia stem cells. These genes have been the focus of our studies to establish better biomarkers and treatment targets. One candidate gene codes for an enzyme with a previously unknown, non-canonical causal role in a specific genetic subtype of leukemia induced by abnormalities of the MLL oncogene. To characterize its molecular contributions, we have identified protein partners that may assist and interact with the enzyme in its oncogenic role. Candidate partners are being investigated for their possible mechanistic roles in leukemia stem cell functions. Another promising candidate identified in our comparative gene expression approach encodes a cell surface protein that is preferentially expressed on leukemia stem cells. We have utilized this cell surface protein as a marker to isolate the rare population of cells in human leukemias with stem cell properties. This technical approach has resulted in the isolation of leukemia stem cell populations that are more highly enriched than those obtained using previous techniques. The highly enriched sub-population of leukemia stem cells has been used for comparative gene expression profiling to identify genes that are differentially expressed between highly matched populations of leukemia cells that are enriched or depleted of leukemia stem cells. Bioinformatics analysis of the dataset has identified major cell cycle differences that distinguish human leukemia stem cells induced by abnormalities of the MLL oncogene. The distinctive cell cycle characteristics of the cells have been confirmed in functional assays for their specific contributions to leukemia stem cell function and leukemia pathogenesis. These studies are the first to mechanistically link a cell surface protein with regulation of self-renewal, a key attribute of leukemia stem cells. Continued characterization of the crucial growth controllers that go awry in blood stem cells to cause leukemia will identify new drug targets for more effective and less toxic treatments against these devastating, life-threatening diseases.
Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05309
Investigator: 
Name: 
Type: 
Co-PI
Type: 
Partner-PI
ICOC Funds Committed: 
$19 999 563
Disease Focus: 
Melanoma
Cancer
Collaborative Funder: 
NIH
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Science has made great progress in the treatment of certain cancers with targeted and combination therapies, yet prolonged remissions or cures are rare because most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer. The study investigators propose to develop an Investigational New Drug (IND) and fully enroll a phase I clinical trial within the grant period to genetically redirect the patient’s immune response to specifically attack the cancer starting from hematopoietic (blood) stem cells (HSC) in patients with advanced forms of the aggressive skin cancer malignant melanoma. Evaluation of immune system reconstitution, effectiveness and immune response during treatment will use imaging with Positron Emission Tomography (PET) scans. The HSC treatment approach has been validated in extensive studies in the laboratory. The investigators of this grant have recently initiated a clinical trial where adult immune cells obtained from blood are genetically modified to become specific killer cells for melanoma. These cells are administered back to patients. The early data from this study is encouraging in terms of the ability to generate these cells, safely administer them to patients leading to beneficial early clinical effects. However, the adult immune cells genetically redirected to attack cancer slowly decrease over time and lose their killer activity, mainly because they do not have the ability to self-renew. The advantage of the proposed HSC method over adult blood cells is that the genetically modified HSC will continuously generate melanoma-targeted immune killer cells, hopefully providing prolonged protection against the cancer. The IND filing with the FDA will use the modified HSC in advanced stage melanoma patients. By the end of year 4, we will have fully accrued this phase 1 clinical trial and assessed the value of genetic modification of HSCs to provide a stable reconstitution of a cancer-fighting immune system. The therapeutic principles and procedures we develop will be applicable to a wide range of cancers and transferrable to other centers that perform bone marrow and HSC transplants. The aggressive milestone-driven IND timeline is based on our: 1) Research that led to the selection and development of a blood cell gene for clinical use in collaboration with the leading experts in the field, 2) Wealth of investigator-initiated cell-based clinical research and the Human Gene Medicine Program (largest in the world with 5% of all patients worldwide), 3) Experience filing a combined 15 investigator initiated INDs for research with 157 patients enrolled in phase I and II trials, and 4) Ability to have leveraged significant institutional resources of on-going HSC laboratory and clinical research contributed ~$2M of non-CIRM funds to pursue the proposed research goals, including the resulting clinical trial.
Statement of Benefit to California: 
Cancer is the leading cause of death in the US and melanoma incidence is increasing fastest (~69K new cases/year). Treatment of metastatic melanoma is an unmet local and national medical need (~9K deaths/year) striking adults in their prime (20-60 years old). Melanoma is the second greatest cancer cause of lost productive years given its incidence early in life and its high mortality once it metastasizes. The problem is severe in California, with large populations with skin types sensitive to the increased exposure to ultraviolet light. Most frequently seen in young urban Caucasians, melanoma also strikes other ethnicities, i.e., steady increases of acral melanoma in Latinos and African-Americans over the past decades. Although great progress has been made in the treatment of certain leukemias and lymphomas with targeted and combination therapies, few options exist for the definitive treatment of late stage solid tumors. When cancers like lung, breast, prostate, pancreas, and melanoma metastasize beyond surgical boundaries, prolonged remissions or cures are rare and most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer. Our proposal, the filing of an IND and the conduct of a phase 1 clinical trial using genetically modified autologous hematopoietic stem cells (HSC) for the immunotherapy of advanced stage melanoma allowing sustained production of cancer-reactive immune cells, has the potential to address a significant and serious unmet clinical need for the treatment of melanoma and other cancers, increase patient survival and productivity, and decrease cancer-related health care costs. The advantage of the proposed HSC methodology over our current work with peripheral blood cells is that genetically modified stem cells will continuously generate melanoma-targeted immune cells in the patient’s body providing prolonged protection against the cancer. The therapeutic principles and procedures developed here will be applicable to a wide range of cancers. Good Manufacturing Practices (GMP) reagents and clinical protocols developed by our team will be transferable to other centers where bone marrow and peripheral blood stem cell transplantation procedures are done.
Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05373
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$109 750
Disease Focus: 
Brain Cancer
Cancer
oldStatus: 
Closed
Public Abstract: 
Glioblastoma multiforme is the most prevalent and aggressive type of brain tumor, and devastating to any patient unfortunate enough to receive its diagnosis. As the most populous state in the nation, more Californians are diagnosed with glioblastoma multiforme than any other state. Over the past 20 years, surgery, radiation therapy and chemotherapy have been utilized with frustrating results. Today, even with the most advanced treatments available, survival rates average only 14-15 months. Our proposed research focuses on a new theory that brain tumor cells are initiated and maintained by a small fraction of cells with stem cell-like properties. This “cancer stem cell” hypothesis states that if this small subset of cancer stem cells could be eliminated then the tumor would cease to grow. Cancer stem cells in glioblastoma have been identified using CD133, a well known marker for isolating normal neural stem cells. The fact that CD133 is present on normal stem cells means that only targeting this molecule would be potentially dangerous. To enhance targeting, we reasoned that a cancer-specific alteration found in glioblastoma could be used as a potential marker for cancer stem cells. EGFRvIII is a specific variant of the normal EGF receptor and is widely found in glioblastoma but is rarely present in normal tissues. We have now shown that tumor cells that express both CD133 and EGFRvIII have the most cancer stem cell properties—more so than cells that have CD133 or EGFRvIII alone. We then developed a “bispecific” antibody that simultaneously recognizes both of these markers and we have shown that this bispecific selectively kills the cancer cells in glioblastoma tumors that express both CD133 and EGFRvIII. However, the bispecific did not kill normal stem cells. These results are very promising and suggest that bispecific can be tested as a therapeutic for glioblastoma. To move this into patients, we will produce large quantities of the bispecific and perform rigorous tests to ensure that it is uniform and has the required properties. We will also determine that it is safe through a combination of cell based and animal studies. Extensive planning will be made for the correct format for the clinical trial to test this molecule. Once the properties of the bispecific are certified and plans for the clinical trial are finalized, we will submit the drug to the FDA for an Investigational New Drug application. Once approved by the FDA, we can then move forward with testing this compound in glioblastoma patients. We are particularly excited about the bispecific as it could serve as the paradigm for a new class of drugs that specifically target cancer stem cells.
Statement of Benefit to California: 
Glioblastoma is a devastating diagnosis. The most common and malignant form of brain cancer, the most aggressive treatments currently available yield an average survival of only 14-15 months. As the most populous state in the nation, more Californians are diagnosed with glioblastoma each year than any other state, with a consequent significant economic toll to the state as well as its emotional toll. As the leader in cutting edge biomedical research, California through CIRM has recognized the unmet need to provide a roadmap for the translation of stem cell research to clinical applications. Through CIRM there is an unparalleled opportunity to foster clearly-defined discovery that will not only benefit Californians with glioblastomas, but potentially those with many other cancers, and ultimately all Californians, through healthier citizens, increased employment opportunities, and reduced economic burdens. We have previously shown that two markers of cancer stem cells, CD133 and EGFRvIII, are tightly associated in glioblastoma tumors. We created a recombinant bispecific antibody (BsAb) selectively targeting CD133 and EGFRvIII. This antibody selectively kills glioblastoma tumor cells but not healthy cells. When glioblastoma cells pre-treated with BsAb were injected into mice, tumor formation was significantly reduced, strongly suggesting that targeting of the EGFRvIII/CD133 cancer stem cell population can inhibit glioblastoma formation. The key objective of our project is to identify efficient and high yield methods for BsAb production, identify an effective dose and route of delivery for the treatment of brain tumors, and evaluate any potential effects on cells/tissues that express CD133. Our goal is to ready the BsAb for investigational new drug-related development. Californians will benefit from this research project in several significant ways. 1) Most importantly, this research has the promise to dramatically extend the long-term survival rates for Californians with glioblastomas, with potential applications to multiple other human cancers. 2) The research will take place in California with direct benefit to the California economy through the hiring of employees and purchase of supplies and reagents. 3) With successful completion of the proposed project, a clinical trial will be the direct next step, requiring additional employees along with associated expenditures. 4) If the therapeutic BsAb generated is commercialized, profits derived from the production of the BsAbs by CIRM policy will result in improved treatments to insured patients and lower cost treatments to the uninsured, thus ultimately benefiting all Californians. 5) Finally, funding this research will help raise awareness of California’s prominence as a national and international leader in stem cell research with the potential to benefit glioblastoma patients world-wide.
Progress Report: 
  • During the funding period, we were able to identify a project manager, Mauri Okamoto-Kearney, MBA who was then able to engage various consultants for all areas needed to write the Disease Team Proposal. We held various meetings with several CROs and CMOs to identify the best facility and processes for carrying out the manufacture and testing of the product. Following our fact gathering process, we used further personnel to write and assemble the final proposal.
Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05309
Investigator: 
ICOC Funds Committed: 
$110 000
Disease Focus: 
Melanoma
Cancer
oldStatus: 
Closed
Public Abstract: 
Science has made great progress in the treatment of certain cancers with targeted and combination therapies, yet prolonged remissions or cures are rare because most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer. The study investigators propose to develop an Investigational New Drug (IND) and fully accrue a phase I clinical trial within the grant period to genetically redirect the patient’s immune response to specifically attack the cancer starting from hematopoietic (blood) stem cells (HSC) in patients with advanced forms of the aggressive skin cancer malignant melanoma. Evaluation of immune system reconstitution, effectiveness and immune response during treatment will use imaging with Positron Emission Tomography (PET) scans. The HSC treatment approach has been validated in extensive studies in the laboratory. The investigators of this grant have recently initiated a clinical trial where adult immune cells obtained from blood are genetically modified to become specific killer cells for melanoma. These cells are administered back to patients. The early data from this study is encouraging in terms of the ability to generate these cells, safely administer them to patients leading to beneficial early clinical effects. However, the adult immune cells genetically redirected to attack cancer slowly decrease over time and lose their killer activity, mainly because they do not have the ability to self-renew. The advantage of the proposed HSC method over adult blood cells is that the genetically modified HSC will continuously generate melanoma-targeted immune killer cells, hopefully providing prolonged protection against the cancer. The IND filing with the FDA will use the modified HSC in advanced stage melanoma patients. By the end of year 4, we will have fully accrued this phase 1 clinical trial and assessed the value of genetic modification of HSCs to provide a stable reconstitution of a cancer-fighting immune system. The therapeutic principles and procedures we develop will be applicable to a wide range of cancers and transferrable to other centers that perform bone marrow and HSC transplants. The aggressive milestone-driven IND timeline is based on our: 1) Research that led to the selection and development of a blood cell gene for clinical use in collaboration with the leading experts in the field, 2) Our wealth of investigator-initiated cell-based clinical research and the Human Gene Medicine Program (largest in the world with 5% of all patients worldwide), 3) Experience filing a combined 15 investigator initiated INDs for research with 157 patients enrolled in phase I and II trials, and 4) Ability to leverage significant institutional resources of on-going HSC laboratory and clinical research and contribute ~$1M of non-CIRM funds to pursue the proposed research goals, including the resulting clinical trial.
Statement of Benefit to California: 
Cancer is the leading cause of death in the US and melanoma incidence is increasing fastest (~69K new cases/year). Treatment of metastatic melanoma is an unmet local and national medical need (~9K deaths/year) striking adults in their prime (20-60 years old). Melanoma is the second greatest cancer cause of lost productive years given its incidence early in life and its high mortality once it metastasizes. The problem is severe in California, with large populations with skin types sensitive to the increased exposure to ultraviolet light. Most frequently seen in young urban Caucasians, melanoma also strikes other ethnicities, i.e., steady increases of acral melanoma in Latinos and African-Americans over the past decades. Although great progress has been made in the treatment of certain leukemias and lymphomas with targeted and combination therapies, few options exist for the definitive treatment of late stage solid tumors. When cancers like lung, breast, prostate, pancreas, and melanoma metastasize beyond surgical boundaries, prolonged remissions or cures are rare and most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer. Our proposal, the filing of an IND and the conduct of a phase 1 clinical trial using genetically modified autologous hematopoietic stem cells (HSC) for the immunotherapy of advanced stage melanoma allowing sustained production of cancer-reactive immune cells, has the potential to address a significant and serious unmet clinical need for the treatment of melanoma and other cancers, increase patient survival and productivity, and decrease cancer-related health care costs. The advantage of the proposed HSC methodology over our current work with peripheral blood cells is that genetically modified stem cells will continuously generate melanoma-targeted immune cells in the patient’s body providing prolonged protection against the cancer. The therapeutic principles and procedures developed here will be applicable to a wide range of cancers. Good Manufacturing Practices (GMP) reagents and clinical protocols developed by our team will be transferable to other centers where bone marrow and peripheral blood stem cell transplantation procedures are done.
Progress Report: 
  • The planning award funds were entirely dedicated to the establishment of the disease team for the full award submission. This has included:
  • - Hiring the project leader, Dr. Phyllis Wu.
  • - Organization of the cell therapy manufacturing, quality assurance, and clinical groups.
  • - A meeting of the external advisory board.
  • - A site visit to the lentiviral vector manufacturing facility.
  • With these activities we were able to assemble and submit the full CIRM DT-2 application to pursue a translational research project based on the genetic programming of hematopoietic stem cells to become cancer-targeted by the insertion of T cell receptor (TCR) genes.
Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05327
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$74 195
Disease Focus: 
Blood Cancer
Cancer
HIV/AIDS
oldStatus: 
Closed
Public Abstract: 
The Human Immunodeficiency Virus (HIV) is still a major health problem. In both developed and underdeveloped nations, millions of people are infected with this virus. HIV infects cells of the immune system, becomes part of the cell’s genetic information, stays there for the rest of the life of these cells, and uses these cells as a factory to make more HIV. In this process, the immune cells get destroyed. Soon a condition called AIDS, the Acquired Immunodeficiency Syndrome sets in where the immune system cannot fight common infections. If left untreated, death from severe infections occurs within 8 to 10 years. Although advances in treatment using small molecule drugs have extended the life span of HIV infected individuals, neither a cure for HIV infection nor a well working vaccine could be developed. Drug treatment is currently the only option to keep HIV infected individuals alive. Patients have to take a combination of drugs daily and reliably for the rest of their lives. If not taken regularly, HIV becomes resistant to the drugs and continues to destroy immune cells. What makes this situation even more complicated is the fact that many patients cannot take these drugs due to severe side effects. Stem cell gene therapy for HIV may offer an alternative treatment. Blood forming stem cells, also called bone marrow stem cells make all blood cells of the body, including immune system cells such as T cells and macrophages that HIV destroys. If “anti-HIV genes” were inserted into the genetic information of bone marrow stem cells, these genes would be passed on to all new immune cells and make them resistant to HIV. Anti-HIV gene containing immune cells can now multiply in the presence of HIV and fight the virus. In previous and current stem cell gene therapy clinical trials for HIV, only one anti-HIV gene has been used. Our approach, however, will use a combination of three anti-HIV genes which are much more potent. They will not only prevent HIV from entering an immune cell but will also prevent HIV from mutating, since it would have to escape the anti-HIV effect of three genes, similar to triple combination anti-HIV drug therapy. To demonstrate safety and effectiveness of our treatment, we will perform a clinical trial in HIV lymphoma patients. In such patients, the destruction of the immune system by HIV led to the development of a cancer of the lymph nodes called B cell lymphoma. High dose chemotherapy together with the transplantation of the patient’s own bone marrow stem cells cures B cell lymphoma. We will insert anti-HIV genes in the patient’s bone marrow stem cells and then transplant these gene containing cells into the HIV infected lymphoma patient. The gene containing bone marrow stem cells will produce a new immune system and newly arising immune cells will be resistant to HIV. In this case, we have not only cured the patient's cancer but have also given the patient an HIV resistant immune system which will be able to fight HIV.
Statement of Benefit to California: 
As of September 30, 2010, over 198,883 cumulative HIV/AIDS cases were reported in California. Another 40,000 un-named cases of HIV were also reported before 2006 although some of them may be duplicates of the named HIV cases. Patients living with HIV/AIDS totaled 108,986 at the end of September 2010. These numbers continue to grow since new cases of HIV and AIDS are being reported on a daily basis and patients now live much longer. In fact, after New York, California has the second highest number of HIV cases in the nation. Although the current and improved anti-retroviral small molecule drugs have prolonged the life of these patients, they still have to deal with the emotional, financial, and medical consequences of this disease. The fear of side effects and the potential generation of drug resistant strains of HIV is a constant struggle that these patients have to live with for the rest of their lives. Furthermore, not every patient with HIV responds to treatment and not every complication of HIV dissipates upon starting a drug regimen. In fact, the risk of some AIDS-related cancers still remains high despite the ongoing drug therapy. Additionally, in the current economic crisis, the financial burden of the long term treatment of these patients on California taxpayers is even more obvious. In 2006, the lifetime cost of taking care of an HIV patient was calculated to be about $618,900. Most of this was related to the medication cost. With the introduction of new HIV medications that have a substantially higher price and with the increase in the survival of HIV/AIDS patients, the cost of taking care of these patients can be estimated to be very high. The proposed budget cuts and projected shortfall in the California AIDS assistant programs such as ADAP will make the situation worse and could result in catastrophic consequences for patients who desperately need this of kind of support. Consequently, improved therapeutic approaches and the focus on developing a cure for HIV infected patients are issues of great importance to the people of California. Our proposed anti-HIV stem cell gene therapy strategy comprises the modification of autologous hematopoietic blood forming stem cells with a triple combination of potent anti-HIV genes delivered by a single lentiviral vector construct. This approach would engineer a patient’s immune cells in a way to make them completely resistant to HIV infection. By transplanting these anti-HIV gene expressing stem cells back into an HIV infected patient, the ability of HIV to further replicate and ravage the patient’s immune system would be diminished. The prospect of such a stem cell based therapy which may require only a single treatment to cure an HIV infected patient and which would last for the life of the individual would be especially compelling to the HIV community and the people of California.
Progress Report: 
  • HIV is still a major health problem. In both developed and underdeveloped nations, millions of people are infected with this virus. If left untreated, death from severe infections occurs within 8 to 10 years. Although advances in treatment using small molecule drugs have extended the life span of HIV infected individuals, neither a cure for HIV infection nor a well working vaccine could be developed. Drug treatment is currently the only option to keep HIV infected individuals alive. Patients have to take a combination of drugs daily and reliably for the rest of their lives. If not taken regularly, HIV becomes active again and may even become resistant to the drugs and continues to destroy immune cells. What makes this situation even more complicated is the fact that many patients cannot take these drugs due to severe side effects. Stem cell gene therapy for HIV may offer an alternative treatment. If “anti-HIV genes” were inserted into the genetic information of bone marrow stem cells, these genes would be passed on to all new immune cells and make them resistant to HIV. Anti-HIV gene containing immune cells can now multiply in the presence of HIV and fight the virus. In our approach, we are planning to use a combination of three anti-HIV genes which are much more potent. They will not only prevent HIV from entering an immune cell but will also prevent HIV from mutating, since it would have to escape the anti-HIV effect of three genes, similar to triple combination anti-HIV drug therapy. To demonstrate safety and effectiveness of our treatment, we have proposed a clinical trial in HIV lymphoma patients with stem cell gene therapy incorporated into their routine treatment with high dose chemotherapy together with the transplantation. The fund provided by CIRM (California Institute for Regenerative Medicine) gave us the opportunity to put together a panel of experts within the University of California at Davis and another panel of international experts in the area of gene therapy (an external advisory board). Intense discussion in multiple meeting with members of these two panels as well as many other meetings with individual researches within our institution resulted in the design of a clinical trial for treating patients with HIV disease using our gene therapy approach. It further helped us to identify the necessary means needed to support such a regulatory intensive gene therapy trial. To be able to recruit enough patients for such a trial, we used the funds from this planning grant for several presentations to our colleagues in other institutions for a multi-institutional clinical trial approach. The funds provided to us through this grant helped to calculate the budget required to 1) finish our application with Federal Drug Administration (FDA) to obtain the appropriate license for starting such a trial and 2) to manufacture the target drug and 3) to run the actual clinical trial. Finally, with the help of this grant, we have put together a CIRM disease grant proposal and have applied for necessary funds based on the above calculation.
  • The original progress report was submitted to the CIRM on March 1st 2012. The no cost extension was requested to perform the necessary work related to further development of our clinical trial before submission to RAC. During this period, in multiple meetings we rewrote our clinical trial based on the comments of our external advisory board and other consultants. We submitted our clinical trial protocol and Appendix M to RAC committee and after receiving their preliminary comments, we formulated our response. As the last step, we presented our clinical trial to the members of RAC committee and received a unanimous approval to move forward with the IND application to FDA.
Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05352
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$65 120
Disease Focus: 
Cancer
oldStatus: 
Closed
Public Abstract: 
A important benefit of the tremendous progress in stem cell research has been the recognition that stem cell pathways are frequently re-activated in cancer cells conferring stem cell-like properties on a subset of tumor cells. This understanding is the basis for the emerging field of cancer stem cell (CSC) research. The cancer stem cell paradigm is a new approach in cancer research that has profound implications for new anti-cancer drug development. It is now widely understood that tumors are comprised of different cell types. Experimental evidence has accumulated from many laboratories indicating that different tumor cells vary dramatically in their ability to grow a new tumor. The tumor cells capable of re-growing a new tumor are the CSCs, whereas the bulk of the tumor cells lack this capacity. This property of seeding new tumor growth is analogous to the growth of distant metastases that is a major cause of mortality in cancer patients. The highly tumorigenic cells CSCs share certain properties with normal stem cells, but have accumulated cancer causing mutations clearly making them abnormal. It is now widely appreciated that may current therapies fail to effectively target the CSC population, and thus the CSCs mediate recurrence of disease after treatment. New drugs that target CSCs to kill them or cause them to differentiate into less dangerous, non-tumorigenic cells have the potential to provide significant benefit to patients and to dramatically improve cancer treatment. This project is focused on developing a new anti-cancer drug that has been shown to effectively block CSC self renewal in a variety of common types of cancer. New therapeutic agents that are effective in targeting cancer stem cells may reduce metastases and relapse after treatment thus providing a chance for improved long term survival of cancer patients. In the first phase of the project, we will complete the manufacturing of the drug for subsequent use in clinical trial and also execute safety studies that are necessary before initiating clinical trials. Next, we will test the safety of the drug in patients in Phase 1 clinical trials. Lastly, we will determine the efficacy in breast cancer patients in Phase 2 trials. This project will utilize innovative clinical trial designs to identify the patient populations most likely to benefit from treatment with this new treatment. We intend to focus our clinical testing on an important subset of women with breast cancer for whom effective therapies are currently lacking. Our project is a unique partnership of industry and academic researchers and clinicians dedicated to bringing new medicines to patients most in need of effective therapy.
Statement of Benefit to California: 
This project will benefit the state of California and its citizens in several significant ways. The goal of the work funded by this grant is to develop a new cancer treatment. This agent attacks cancer stem cells - the most dangerous type of tumor cells because they have the unique ability to resist many current therapies and re-grow and metastasize to distant sites in the body. The funds from this study will be used to support innovative drug development and clinical testing in women with advanced breast cancer. Thus, this therapy will benefit cancer patients with a critical need for new treatment options. We have observed that agents that reduce cancer stem cells in tumors also inhibit the spread of metastatic disease. Patients with advanced cancers which have disseminated to distant organs typically require high cost hospital stays. Our new treatment is intended to ameliorate the incidence and relapse of metastatic cancer, thus reducing the requirement for hospitalization and associated specialized care for this class of advanced cancer patients. In addition to the medical benefits of this project, funds from this grant will create and maintain high quality jobs in the state of California. California has been a recognized leader in biomedical research over the past several decades because of its excellent academic institutions and innovative companies attracting researchers from all over the country and the world. Many companies have made significant investments in establishing research facilities in California. Thus, biomedical research generates significant economic activity in the state. Continued leadership in the life sciences field relies on being at the forefront of cutting edge fields that are focal points of research interest and investment. Novel anti-cancer therapeutics, in general, and cancer stem cell-based therapeutic approaches, in particular, are excellent examples of important and innovative directions in drug development. CIRM will provide an important source of funding to support cancer stem cell therapeutics which hold the promise of becoming breakthrough medications in cancer treatment.
Progress Report: 
  • Our project is focused on developing a new anti-cancer drug that has been shown to effectively block cancer stem cell (CSC) self renewal in a variety of major tumor types. During the reporting period our group made significant advances on several fronts in advancing our novel stem cell directed therapy toward clinical development. In particular, we have associated cancer causing mutations in breast cancer in the molecular target of our therapeutic and shown that tumors bearing this type of mutation are exquisitely sensitive to our treatment. Based on this discovery, we have developed methodologies and reagents to identify patients who are most likely to benefit from treatment with our agent. Thus, this project is an excellent example of how "personalized medicine" is becoming a reality in cancer drug development. Furthermore, our results highlight the promise of targeting inappropriate activation of stem cell pathways as new strategy in cancer treatment.
  • During the reporting period we have assembled an experienced team of scientists and clinicians at our institution and also at collaborating institutions to execute the pre-clinical and clinical development of our new anti-cancer treatment. We have developed a detailed clinical strategy which involves a close collaboration between academic medical centers and the biotech industry. We have planned a series of clinical trials which will test the safety and efficacy of our anti-cancer drug and also test our hypothesis regarding selecting patients most likely to respond to treatment. This trials will take place at multiple sites including several in California.
  • In addition, we have made tremendous and tangible progress in advancing our therapeutic toward clinical testing. These steps include the completion of GMP manufacture of the drug for IND-enabling safety studies and for use in subsequent Phase 1 clinical trials and the initiation of IND-enabling safety studies.
Funding Type: 
Basic Biology III
Grant Number: 
RB3-05217
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$1 375 983
Disease Focus: 
Blood Cancer
Cancer
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
The clinical potential of pluripotent stem cells for use in regenerative medicine will be realized only when the process by which tissues are generated from these cells is significantly more efficient and controlled than is currently the case. Fundamental questions remain about the mechanisms by which pluripotent stem cells differentiate into mature tissue. The overall goal of this research proposal is to discover if the cell types produced during differentiation of PSC produce the microenvironment needed for specialized tissue stem cells to develop. To approach this question we will use the hematopoietic (“blood-forming”) system as our model, as it is the best characterized tissue in terms of differentiation pathways and offers a range of unique technical tools with which to rigorously study questions of differentiation. Adult hematopoietic stem cells survive and grow in the bone marrow only if they are physically close to specialized cell types, the so-called hematopoietic stem cell “niche”. We hypothesize that hematopoietic stem cells are not produced from pluripotent cells because the cells that form the niche and provide the necessary signals are not present during this early stage of differentiation. Our research proposal has three specific aims. The first aim is to determine if a single cell type derived from pluripotent cells can generate both blood cells and the cells of the hematopoietic niche. The second aim is to identify the types of niche cells produced from pluripotent cells and define how each of them affect the growth of adult stem cells. In the third aim, the cell types that are found in aim 2 to best support adult hematopoiesis, will then be tested for their ability to promote the production of hematopoietic stem cells from pluripotent stem cells. The findings from these studies will have broad applicability to the production of other types of tissues from pluripotent stem cells, all of which have stem cells that require interaction with a specialized niche. In addition to the biological questions explored in this proposal, our focus on the blood system has direct clinical relevance to the field of bone marrow and cord blood transplantation. The development of a human hematopoietic niche from pluripotent stem cells could potentially be used to expand hematopoietic stem cells from adult tissues like cord blood. Most importantly, the ability to control differentiation from pluripotent stem cells into the blood lineage could provide an unlimited source of matched cells for transplantation for patients with leukemia and other diseases of the bone marrow and the immune system who currently lack suitable donors.
Statement of Benefit to California: 
The unique combination of pluripotentiality and unlimited capacity for proliferation has raised the hope that pluripotent stem cells will one day provide an inexhaustible source of tissue for transplantation and regeneration. Diseases that might be treated from such tissues affect millions of Californians and their families. However, much is still to be learned about the mechanisms by which pluripotent stem cells differentiate into mature tissue. The clinical potential of pluripotent stem cells for regenerative medicine will be realized only when the process by which tissues are generated from these cells is significantly more efficient and better controlled than is currently the case. The research proposed in this application has broad potential benefits for Californians both through the biological questions it will answer and the relevance of these studies for clinical translation. Our goal is to understand the way the microenvironment influences tissue production from pluripotent stem cells, a critical issue for the field of stem cell biology. Specifically we will explore the question- Do the cell types produced during differentiation of pluripotent stem cells produce an adequate microenvironment for the differentiation of tissue or are some cells inhibitory to tissue production? Our approach to these questions will be to use the hematopoietic (“blood-forming”) system as our model, as it is the best characterized tissue in terms of differentiation and offers a range of unique technical tools with which to study these questions rigorously. However, the fundamental concepts formed from these studies will have great relevance for the clinical production of other types of tissues from pluripotent stem cells, such as islets, neural cells and cardiac muscle. In addition to the broad biological questions explored in this proposal, our focus on the blood system has direct clinical relevance to the field of bone marrow and cord blood transplantation. One goal in the proposal is to generate a cellular platform from pluripotent stem cells that will create an environment in which adult blood stem cells can grow and be expanded. Cell numbers collected from cord blood at birth are often insufficient for transplantation in adult patients and older children. The development of a human cell culture system that could expand the number of cord blood stem cells would provide new opportunities for transplantation for patients with leukemia and other diseases of the bone marrow and the immune system who currently lack suitable donors. All scientific findings and technical tools developed in this proposal will be made available to researchers throughout California, under the guidelines from the California Institute of Regenerative Medicine.
Progress Report: 
  • The clinical potential of pluripotent stem cells for use in regenerative medicine will be realized only when the process by which tissues are generated from these cells is significantly more efficient and controlled than is currently the case. Fundamental questions remain about the mechanisms by which pluripotent stem cells differentiate into mature tissue. The overall goal of this research proposal is to discover if the cell types produced during differentiation of PSC produce the microenvironment needed for specialized tissue stem cells to develop.
  • To approach this question we use the hematopoietic (“blood-forming”) system as our model, as it is the best characterized tissue in terms of differentiation pathways and offers a range of unique technical tools with which to rigorously study questions of differentiation. Adult hematopoietic stem cells survive and grow in the bone marrow only if they are physically close to specialized cell types, the so-called hematopoietic stem cell “niche”. We hypothesize that hematopoietic stem cells are not produced from pluripotent cells because the cells that form the niche and provide the necessary signals are not present during this early stage of differentiation.
  • Our research proposal has three specific aims. The first aim is to determine if a single cell type derived from pluripotent cells can generate both blood cells and the cells of the hematopoietic niche. The second aim is to identify the types of niche cells produced from pluripotent cells and define how each of them affect the growth of adult stem cells. In the third aim, the cell types that are found in aim 2 to best support adult hematopoiesis, will then be tested for their ability to promote the production of hematopoietic stem cells from pluripotent stem cells.
  • During the first year of support, we have made significant progress in the first two specific aims. We have developed a method that allows us to track the common origin of the blood forming cells and their microenvironment. We also have identified subsets of cells generated from pluripotent cells that have distinct functions in blood formation. Our plan during the next year is to fully characterize these subsets to understand how they function, and to improve our methods to expand them in culture.
  • The clinical potential of pluripotent stem cells for use in regenerative medicine will be realized only when the process by which tissues are generated from these cells is significantly more efficient and controlled than is currently the case. Fundamental questions remain about the mechanisms by which pluripotent stem cells differentiate into mature tissue. The overall goal of this research proposal is to discover if the cell types produced during differentiation of PSC produce the microenvironment needed for specialized tissue stem cells to develop.
  • To approach this question we use the hematopoietic (“blood-forming”) system as our model, as it is the best characterized tissue in terms of differentiation pathways and offers a range of unique technical tools with which to rigorously study questions of differentiation. Adult hematopoietic stem cells (HSC) survive and grow in the bone marrow only if they are physically close to specialized cell types, the so-called hematopoietic stem cell “niche”. We hypothesize that hematopoietic stem cells are not produced from pluripotent cells because the cells that form the niche and provide the necessary signals are not present during this early stage of differentiation.
  • Our research proposal has three specific aims. The first aim is to determine if a single cell type derived from pluripotent cells can generate both blood cells and the cells of the hematopoietic niche. The second aim is to identify the types of niche cells produced from pluripotent cells and define how each of them affect the growth of adult stem cells. In the third aim, the cell types that are found in aim 2 to best support adult hematopoiesis, will then be tested for their ability to promote the production of hematopoietic stem cells from pluripotent stem cells.
  • During the second year of support, we have made significant progress in all three specific aims. We continue to refine our method that allows us to track the common origin of the blood forming cells and their microenvironment during development. We have identified subsets of cells generated from pluripotent cells that can support cord blood HSC and now we are determining the mechanisms by which these cells act and how they can be best used to support HSC that develop from PSC.
  • The clinical potential of pluripotent stem cells for use in regenerative medicine will be realized only when the process by which tissues are generated from these cells is significantly more efficient and controlled than is currently the case. Fundamental questions remain about the mechanisms by which pluripotent stem cells differentiate into mature tissue. The overall goal of this research proposal is to discover if the cell types produced during differentiation of PSC produce the microenvironment needed for specialized tissue stem cells to develop.
  • To approach this question we use the hematopoietic (“blood-forming”) system as our model, as it is the best characterized tissue in terms of differentiation pathways and offers a range of unique technical tools with which to rigorously study questions of differentiation. Adult hematopoietic stem cells (HSC) survive and grow in the bone marrow only if they are physically close to specialized cell types, the so-called hematopoietic stem cell “niche”. We hypothesize that hematopoietic stem cells are not produced from pluripotent cells because the cells that form the niche and provide the necessary signals are not present during this early stage of differentiation.
  • Our research proposal has three specific aims. The first aim is to determine if a single cell type derived from pluripotent cells can generate both blood cells and the cells of the hematopoietic niche. The second aim is to identify the types of niche cells produced from pluripotent cells and define how each of them affect the growth of adult stem cells. In the third aim, the cell types that are found in aim 2 to best support adult hematopoiesis, will then be tested for their ability to promote the production of hematopoietic stem cells from pluripotent stem cells.
  • During the third year of support, we have made significant progress in all three specific aims. We have now completed our studies that track the common origin of the blood forming cells and their microenvironment. We have performed functional studies to identify which of the cell types that we generate from pluripotent cells support HSC when grown in culture, and which do not. Finally we have performed gene expression analyses on these different cell types to understand the molecular pathways that they use to support HSC in culture.

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