Cancer

Coding Dimension ID: 
280
Coding Dimension path name: 
Cancer

Clinical Development of an N-cadherin Antibody to Target Cancer Stem Cells

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06867
ICOC Funds Committed: 
$4 075 668
Disease Focus: 
Prostate Cancer
Cancer
Stem Cell Use: 
Cancer Stem Cell
oldStatus: 
Closed
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.

Targeting glioma cancer stem cells with receptor-engineered self-renewing memory T cells

Funding Type: 
Early Translational III
Grant Number: 
TR3-05641
ICOC Funds Committed: 
$5 217 004
Disease Focus: 
Brain Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 
While current treatment strategies for high-grade glioma can yield short term benefits, their inability to eradicate the highly tumorigenic cancer stem cell population results in disease recurrence in the vast majority of patients. Stem cells and some cancer cells (the targets of our therapy) share many common characteristics, including the ability to self-renew and grow indefinitely. These cancer stem cells are also resistant to many standard therapies including radiation and chemotherapy, creating a critical need for novel therapies that will efficiently eliminate this cell population. We propose here to develop and optimize a therapeutic strategy, termed “adoptive T cell therapy", that will eliminate the brain tumor stem cell population by re-directing a patient’s immune cells, specifically T cells, to recognize and destroy tumor stem cells. Our goal is a therapy in which a single administration of tumor-specific T cells results in long-term anti-glioma protection. Our approach builds on previous findings that T cells, when reprogrammed, can potently kill glioma stem cells. Furthermore, we will exploit the self-renewing stem cell-like properties of a defined T cell population (central memory T cells) to establish reservoirs of long-lasting tumor-directed T cells in patients with glioma, and thereby achieve durable tumor regression with a glioma-specific T cell product. Our findings can then be applied to cancers besides glioma, including tumors that metastasize to brain.
Statement of Benefit to California: 
The goal of this project is to develop a novel and promising immunotherapy utilizing genetically modified T cells to target glioma stem cells in order to improve cure rates for patients with high-grade malignant glioma. Our strategy, in which a single administration of tumor-specific T cells results in long-term anti-glioma protection, has the potential to provide significant therapeutic benefit to patients with brain tumors, for which there is a dearth of effective treatment options. Further, the tumor-specificity of this therapy is intended to improve the quality of life for patients with high-grade gliomas by reducing treatment related side-effects of conventional therapies. Moreover, due to the high cost hospital stays and treatments usually required for patients with advanced disease, this therapy, by generating long-lasting anti-cancer immunity, has the potential to significantly reduce the costs of health care to California and its citizens. Carrying out these proposed studies will have further economic benefit for California through the creation and maintenance of skilled jobs, along with the purchasing of equipment and supplies from in-state companies. This project will also yield long-reaching benefit through continuing to build the larger CIRM community that is establishing California as a leader in stem-cell and biomedical research both nationally and internationally.
Progress Report: 
  • While current treatment strategies for high-grade glioma can yield short term benefits, their inability to eradicate the highly tumorigenic cancer stem cell population results in disease recurrence in the vast majority of patients. Stem cells and some cancer cells (the targets of our therapy) share many common characteristics, including the ability to self-renew and grow indefinitely. These stem cell-like cancer cells are also resistant to many standard therapies including radiation and chemotherapy, creating a critical need for novel therapies that will efficiently eliminate this cell population. The goal of this project is to develop and optimize a therapeutic strategy, termed “adoptive T cell therapy,” that will eliminate the brain tumor stem cell population by re-directing a patient’s immune cells, specifically T cells, to recognize and destroy tumor stem cells. Our goal is a therapy in which a single administration of tumor-specific T cells results in long-term anti-glioma protection. Our approach builds on our previous pre-clinical and clinical findings that T cells, when reprogrammed, can potently kill glioma stem cells.
  • Over the past year, our group has developed and characterized an optimized next-generation adoptive T cell therapy platform for targeting the glioma-associated antigen IL13Rα2. As such, T cells were modified to express a chimeric antigen receptor (CAR) to recognize and kill IL13Rα2-expressing glioma cells. This T cell platform incorporates several improvements in CAR design and T cell engineering, including improved receptor signaling and the utilization of central memory T cells (Tcm) as the starting cell population for CAR-engineering for enhanced long-term persistence of the cells after they are administered to patients. Importantly, we now demonstrate that this optimized IL13Rα2-specific CAR Tcm therapeutic product mediates superior antitumor efficacy and improved T cell persistence as compared to our previous first-generation IL13Rα2-specific T cells. These findings are significant as they suggest the potential for improving the transient anti-glioma responses for patients, as observed in two Phase I clinical trials by our group at City of Hope, with this optimized next-generation platform.
  • The variability of gliomas, including the known differences between populations of glioma stem-like cells, is a critical barrier to the development of a therapy with the potential to mediate complete and durable remission of this disease. We have therefore hypothesized that a multi-targeted therapeutic approach will be required to achieve elimination of glioma stem-like cells and achieve longer lasting regression of high-grade glioma. To devise an effective multi-target therapy, one must first identify the potentially useful T cell target antigens and variations in their expression between patients and within individual tumors. The ideal target will be highly expressed on tumor cells, including stem-like cells, and not found on normal brain or other tissues. To this end, we have assembled a cohort of 35 patient samples in commercial tissue arrays and 45 patient specimens from the CoH Department of Pathology. Within this group of 80 patient tumors we have begun to examine expression of potential T cell targets, such as IL13Rα2, HER2, EGFR, and others. The goal is to find a set of target antigens that would encompass the maximum number of tumors and, in particular, the cancer stem-like cells within an individual tumor.
  • Our progress thus far has set the stage for our team to develop a potent multi-antigen specific T cell therapy that can “box-in” tumor variability. This clinically translatable platform has the potential to provide new treatment options for this devastating disease.

Recombinant Bispecific Antibody Targeting Cancer Stem Cells for the Therapy of Glioblastoma

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05373
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.

Genetic Re-programming of Stem Cells to Fight Cancer

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05309
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.

RUNNING TITLE: Stem Cell Gene Therapy for HIV in AIDS Lymphoma Patients

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05327
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.

[REDACTED]: A New Cancer Therapeutic to Reduce CSC Frequency

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05352
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.

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