Cancer

Coding Dimension ID: 
280
Coding Dimension path name: 
Cancer
Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-06965
Investigator: 
Institution: 
Type: 
PI
Institution: 
Type: 
Co-PI
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$12 726 396
Disease Focus: 
Cancer
Solid Tumor
Blood Cancer
Collaborative Funder: 
UK
Stem Cell Use: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 
Most normal tissues are maintained by a small number of stem cells that can both self-renew to maintain stem cell numbers, and also give rise to progenitors that make mature cells. We have shown that normal stem cells can accumulate mutations that cause progenitors to self-renew out of control, forming cancer stem cells (CSC). CSC make tumors composed of cancer cells, which are more sensitive to cancer drugs and radiation than the CSC. As a result, some CSC survive therapy, and grow and spread. We sought to find therapies that include all CSC as targets. We found that all cancers and their CSC protect themselves by expressing a ‘don’t eat me’ signal, called CD47, that prevents the innate immune system macrophages from eating and killing them. We have developed a novel therapy (anti-CD47 blocking antibody) that enables macrophages to eliminate both the CSC and the tumors they produce. This anti-CD47 antibody eliminates human cancer stem cells when patient cancers are grown in mice. At the time of funding of this proposal, we will have fulfilled FDA requirements to take this antibody into clinical trials, showing in animal models that the antibody is safe and well-tolerated, and that we can manufacture it to FDA specifications for administration to humans. Here, we propose the initial clinical investigation of the anti-CD47 antibody with parallel first-in-human Phase 1 clinical trials in patients with either Acute Myelogenous Leukemia (AML) or separately a diversity of solid tumors, who are no longer candidates for conventional therapies or for whom there are no further standard therapies. The primary objectives of our Phase I clinical trials are to assess the safety and tolerability of anti-CD47 antibody. The trials are designed to determine the maximum tolerated dose and optimal dosing regimen of anti-CD47 antibody given to up to 42 patients with AML and up to 70 patients with solid tumors. While patients will be clinically evaluated for halting of disease progression, such clinical responses are rare in Phase I trials due to the advanced illness and small numbers of patients, and because it is not known how to optimally administer the antibody. Subsequent progression to Phase II clinical trials will involve administration of an optimal dosing regimen to larger numbers of patients. These Phase II trials will be critical for evaluating the ability of anti-CD47 antibody to either delay disease progression or cause clinical responses, including complete remission. In addition to its use as a stand-alone therapy, anti-CD47 antibody has shown promise in preclinical cancer models in combination with approved anti-cancer therapeutics to dramatically eradicate disease. Thus, our future clinical plans include testing anti-CD47 antibody in Phase IB studies with currently approved cancer therapeutics that produce partial responses. Ultimately, we hope anti-CD47 antibody therapy will provide durable clinical responses in the absence of significant toxicity.
Statement of Benefit to California: 
Cancer is a leading cause of death in the US accounting for approximately 30% of all mortalities. For the most part, the relative distribution of cancer types in California resembles that of the entire country. Current treatments for cancer include surgery, chemotherapy, radiation therapy, biological therapy, hormone therapy, or a combination of these interventions ("multimodal therapy"). These treatments target rapidly dividing cells, carcinogenic mutations, and/or tumor-specific proteins. A recent NIH report indicated that among adults, the combined 5-year relative survival rate for all cancers is approximately 68%. While this represents an improvement over the last decade or two, cancer causes significant morbidity and mortality to the general population as a whole. New insights into the biology of cancer have provided a potential explanation for the challenge of treating cancer. An increasing number of scientific studies suggest that cancer is initiated and maintained by a small number of cancer stem cells that are relatively resistant to current treatment approaches. Cancer stem cells have the unique properties of continuous propagation, and the ability to give rise to all cell types found in that particular cancer. Such cells are proposed to persist in tumors as a distinct population, and because of their increased ability to survive existing anti-cancer therapies, they regenerate the tumor and cause relapse and metastasis. Cancer stem cells and their progeny produce a cell surface ‘invisibility cloak’ called CD47, a ‘don’t eat me signal’ for cells of the native immune system to counterbalance ‘eat me’ signals which appear during cancer development. Our anti-CD47 antibody counters the ‘cloak’, enabling the patient’s natural immune system to eliminate the cancer stem cells and cancer cells. Our preclinical data provide compelling support that anti-CD47 antibody might be a treatment strategy for many different cancer types, including breast, bladder, colon, ovarian, glioblastoma, leiomyosarcoma, squamous cell carcinoma, multiple myeloma, lymphoma, and acute myelogenous leukemia. Development of specific therapies that target all cancer stem cells is necessary to achieve improved outcomes, especially for sufferers of metastatic disease. We hope our clinical trials proposed in this grant will indicate that anti-CD47 antibody is a safe and highly effective anti-ancer therapy that offers patients in California and throughout the world the possibility of increased survival and even complete cure.
Funding Type: 
Genomics Centers of Excellence Awards (R)
Grant Number: 
GC1R-06673-C
Investigator: 
ICOC Funds Committed: 
$40 000 000
Disease Focus: 
Brain Cancer
Cancer
Developmental Disorders
Cancer
Toxicity
Public Abstract: 
The Center of Excellence in Stem Cell Genomics will bring together investigators from seven major California research institutions to bridge two fields – genomics and pluripotent stem cell research. The projects will combine the strengths of the center team members, each of whom is a leader in one or both fields. The program directors have significant prior experience managing large-scale federally-funded genomics research programs, and have published many high impact papers on human stem cell genomics. The lead investigators for the center-initiated projects are expert in genomics, hESC and iPSC derivation and differentiation, and bioinformatics. They will be joined by leaders in stem cell biology, cancer, epigenetics and computational systems analysis. Projects 1-3 will use multi-level genomics approaches to study stem cell derivation and differentiation in heart, tumors and the nervous system, with implications for understanding disease processes in cancer, diabetes, and cardiac and mental health. Project 4 will develop novel tools for computational systems and network analysis of stem cell genome function. A state-of-the-art data management program is also proposed. This research program will lead the way toward development of the safe use of stem cells in regenerative medicine. Finally, Center resources will be made available to researchers throughout the State of California through a peer-reviewed collaborative research program.
Statement of Benefit to California: 
Our Center of Excellence for Stem Cell Genomics will help California maintain its position at the cutting edge of Stem Cell research and greatly benefit California in many ways. First, diseases such as cardiovascular disease, cancer, neurological diseases, etc., pose a great financial burden to the State. Using advanced genomic technologies we will learn how stem cells change with growth and differentiation in culture and can best be handled for their safe use for therapy in humans. Second, through the collaborative research program, the center will provide genomics services to investigators throughout the State who are studying stem cells with a goal of understanding and treating specific diseases, thereby advancing treatments. Third, it will employ a large number of “high tech” individuals, thereby bringing high quality jobs to the state. Fourth, since many investigators in this center have experience in founding successful biotech companies it is likely to “spin off” new companies in this rapidly growing high tech field. Fifth, we believe that the iPS and information resources generated by this project will have significant value to science and industry and be valuable for the development of new therapies. Overall, the center activities will create a game-changing network effect for the state, propelling technology development, biological discovery and disease treatment in the field.
Funding Type: 
Genomics Centers of Excellence Awards (R)
Grant Number: 
GC1R-06673-A
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$40 000 000
Disease Focus: 
Brain Cancer
Cancer
Developmental Disorders
Heart Disease
Cancer
Genetic Disorder
Stem Cell Use: 
iPS Cell
Embryonic Stem Cell
Adult Stem Cell
Cancer Stem Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 
The Center of Excellence in Stem Cell Genomics will bring together investigators from seven major California research institutions to bridge two fields – genomics and pluripotent stem cell research. The projects will combine the strengths of the center team members, each of whom is a leader in one or both fields. The program directors have significant prior experience managing large-scale federally-funded genomics research programs, and have published many high impact papers on human stem cell genomics. The lead investigators for the center-initiated projects are expert in genomics, hESC and iPSC derivation and differentiation, and bioinformatics. They will be joined by leaders in stem cell biology, cancer, epigenetics and computational systems analysis. Projects 1-3 will use multi-level genomics approaches to study stem cell derivation and differentiation in heart, tumors and the nervous system, with implications for understanding disease processes in cancer, diabetes, and cardiac and mental health. Project 4 will develop novel tools for computational systems and network analysis of stem cell genome function. A state-of-the-art data management program is also proposed. This research program will lead the way toward development of the safe use of stem cells in regenerative medicine. Finally, Center resources will be made available to researchers throughout the State of California through a peer-reviewed collaborative research program.
Statement of Benefit to California: 
Our Center of Excellence for Stem Cell Genomics will help California maintain its position at the cutting edge of Stem Cell research and greatly benefit California in many ways. First, diseases such as cardiovascular disease, cancer, neurological diseases, etc., pose a great financial burden to the State. Using advanced genomic technologies we will learn how stem cells change with growth and differentiation in culture and can best be handled for their safe use for therapy in humans. Second, through the collaborative research program, the center will provide genomics services to investigators throughout the State who are studying stem cells with a goal of understanding and treating specific diseases, thereby advancing treatments. Third, it will employ a large number of “high tech” individuals, thereby bringing high quality jobs to the state. Fourth, since many investigators in this center have experience in founding successful biotech companies it is likely to “spin off” new companies in this rapidly growing high tech field. Fifth, we believe that the iPS and information resources generated by this project will have significant value to science and industry and be valuable for the development of new therapies. Overall, the center activities will create a game-changing network effect for the state, propelling technology development, biological discovery and disease treatment in the field.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05641
Investigator: 
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.
  • While current treatment strategies for glioblastoma (GBM) 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 administration of tumor-specific T cells targeting combinations of antigens expressed on the cell surface of glioma stem-like 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.
  • Thus far, 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 over previous versions, including improved receptor signaling and the utilization of central memory T cells (Tcm) as the starting cell population for CAR-engineering (enhancing 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. We further demonstrate that intracranial (i.c.) delivery of the IL13Rα2-specific CAR T cells outperforms intravenous (i.v.) delivery in orthtotopic mouse models of human glioblastoma, providing the clinical rational for local i.c. delivery. These findings are significant as they suggest the potential of this optimized next-generation platform to improve upon the transient anti-glioma patient responses observed in two Phase I clinical trials completed by our group at City of Hope. Based on these earlier results we have submitted an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) to initiate a single agent IL13Rα2-specific CAR T cell clinical trial. This clinical trial will provide a foundation for the ultimate goal of this CIRM ET award: development of a combination CAR T cell approach to overcome the high-degree of GBM heterogeneity.
  • This antigenic variability of gliomas, including differences between populations of glioma stem-like cells, is a critical barrier to the development of an immunotherapy with the potential to mediate complete and durable disease remission. We hypothesize 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, we are first identifying potentially useful T cell target antigens, and assessing variations in their expression between patients and within individual tumors. Ideal targets 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 been examining expression of potential T cell targets, such as IL13Rα2, HER2, EGFR/EGFRvIII, and others. Our goal is to define a set of target antigens encompassing the maximum number of tumors and, in particular, the cancer stem-like cells within individual tumors. Based on this analysis, we are currently developing and optimizing CAR T cells targeting HER2 and EGFRvIII.
  • Our progress is thus continuing to set the stage for developing a potent multi-antigen specific T cell therapy that can “box-in” tumor variability. Our clinically translatable platform has the potential to provide new treatment options for this devastating disease.
Funding Type: 
Research Leadership 1
Grant Number: 
LA1-01747
Investigator: 
ICOC Funds Committed: 
$5 919 616
Disease Focus: 
Brain Cancer
Cancer
Cell Line Generation: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 
Stem cells have the remarkable ability to renew themselves and to generate multiple different cell types. This allows them to generate normal tissues during development and to repair tissues following injury, but at the same time, renders them highly susceptible to mutations that can result in cancer. Only by understanding the signals that control growth and differentiation of stem cells can we learn to harness their regenerative capacity and restrain their malignant potential. The research described in this proposal is aimed at elucidating the role of neural stem cells in development, regeneration and tumor formation in the cerebellum. Our previous studies identified a population of neural stem cells in the developing cerebellum. We now propose to use genetic approaches to mark these cells and identify the cell types that they generate during normal development. In addition, we plan to examine the capacity of these cells to regenerate the cerebellum following radiation. Finally, we propose to study the ability of these cells to give rise to brain tumors, and use the models that result from these studies to develop and test novel approaches to therapy. These studies will pave the way towards use of stem cells for repair of neurological damage and help develop more effective treatments for patients with brain tumors.
Statement of Benefit to California: 
We have previously identified a novel population of neural stem cells in the cerebellum. This proposal is focused on understanding the role of these cells in normal development, regeneration and tumor formation. It has the potential to benefit California in a number of important ways. 1. Treatment of Brain Damage: Radiation is the most commonly used treatment for brain tumors, and children who receive this treatment often suffer severe side effects, including a progressive loss of intellectual function. By studying the ability of cerebellar stem cells to repair brain tissue, we will advance the treatment of patients suffering from brain damage due to radiation therapy. The knowledge we gain may also be more broadly applicable, advancing the use of stem cells to repair damage due to congenital brain disorders, trauma and stroke. 2. Treatment of Brain Tumors: Medulloblastoma and astrocytoma are the most common brain tumors in children. By examining the role of stem cells in development of these tumors, we will deepen our understanding of how brain tumors form, and develop novel approaches to treating them. Moreover, we will create new model systems that can be used to test these therapies, with the hope of moving the most effective ones forward towards trials in patients. 3. Technology: Our research will culminate in the invention and generation of new drugs and approaches to therapy that will be made available for licensing by the academic institutions in California, such as {REDACTED} and its collaborators, and developed by pharmaceutical companies based in the State. 4. Collaboration: Our work is multidisciplinary and translational in nature. As such, it will require collaboration with other investigators, including stem cell biologists, neurobiologists, cancer biologists and chemists involved in experimental therapeutics. Once discoveries are made that may be of benefit to patients, we will also work with clinicians to move these discoveries towards the clinic. Californians will be the likely first beneficiaries of these therapies because the clinical trials will be conducted here and we will make an effort to make sure that Californians have immediate access to these therapies when they become standard. By bringing together investigators from various fields and focusing their attention on clinically relevant problems, our studies will advance the translational potential of stem cell research in California.
Progress Report: 
  • The goal of our studies is to determine the role of neural stem cells in the development, regeneration and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • The aims of our studies are: (1) To identify the cell types generated by cerebellar stem cells during normal development; (2) To determine the capacity of cerebellar stem cells to repair damage caused by radiation or disease; and (3) To determine whether cerebellar stem cells can give rise to the pediatric brain tumor medulloblastoma.
  • We have made significant progress toward our goals over the last year. In particular, we have identified genetic markers that allow us to trace the fate of cerebellar stem cells during normal development. In addition, we have demonstrated that cerebellar stem cells carrying cancer-causing genes can give rise to medulloblastoma. Importantly, this finding has allowed us to create stem cell-based models of medulloblastoma that can be used to test drugs that may be useful for treating the disease. Over the next few years, we hope to use this information to develop more effective therapies for children suffering from medulloblastoma.
  • The goal of our studies is to determine the role of neural stem cells in the development, regeneration and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • The aims of our studies are: (1) To identify the cell types generated by cerebellar stem cells during normal development; (2) To determine the capacity of cerebellar stem cells to repair damage caused by radiation or disease; and (3) To determine whether cerebellar stem cells can give rise to the pediatric brain tumor medulloblastoma.
  • We have made significant progress toward our goals over the last year. In particular, we have identified genetic markers that allow us to trace the fate of cerebellar stem cells during normal development. In addition, we have demonstrated that cerebellar stem cells carrying cancer-causing genes can give rise to medulloblastoma. Importantly, this finding has allowed us to create stem cell-based models of medulloblastoma that can be used to test drugs that may be useful for treating the disease. Our screening efforts over the past year have begun to identify compounds that inhibit the growth of human medulloblastoma tumor cells. Over the next few years, we hope to use this information to develop more effective therapies for children suffering from medulloblastoma.
  • The goal of our studies is to determine the role of neural stem cells in development, regeneration, and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • We have made significant progress towards our goals during the past year. We have identified new drugs that potently inhibit the growth of medulloblastoma, the most common malignant brain tumor in children. This work could lead to development of new, more effective therapies for medulloblastoma in patients. In addition, we have developed new models for several types of brain tumors, including one that resembles the most aggressive form of medulloblastoma, and several that model choroid plexus tumors. These models are valuable resources for studying the biology and therapeutic responsiveness of these diseases. Over the next few years, we will continue in our efforts to develop more effective therapies for children suffering from aggressive brain tumors.
  • The goal of our studies is to elucidate the role of neural stem cells in development, regeneration, and tumor formation in the cerebellum. By understanding the role of stem cells, we hope to learn to use them for repair of neurological damage and to develop more effective treatments for patients with brain tumors.
  • We have made significant progress towards our goals in the past year. Using animal models developed in our lab, we have uncovered new mechanisms and pathways that drive the growth and metastasis of medulloblastoma, the most common malignant brain tumor in children. In addition, we have identified molecular pathways that are de-regulated in choroid plexus carcinoma, a rare brain tumor with a poor prognosis that occurs most frequently in children. Our work has also led to the identification of new drugs that inhibit the growth of medulloblastoma and choroid plexus carcinoma. In the coming year, we will continue in our efforts to understand these aggressive cancers and develop new, more effective therapies for children who suffer from them.
Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06209
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$1 382 400
Disease Focus: 
Cancer
Prostate Cancer
Stem Cell Use: 
Cancer Stem Cell
oldStatus: 
Active
Public Abstract: 
Progress from our group and others has led to the identification of normal prostate tissue stem cells and the definition of important signaling pathways that regulate their growth and maintenance. Human cancers utilize these same pathways to promote malignancy and drive tumor progression. Our recent studies have uncovered an important regulatory molecule (Trop2) that is expressed on a subset of prostate cancer cells capable of regenerating tumors. Trop2 expression is selected for in advanced disease and predicts poor prognosis for many tumors including prostate, ovarian, pancreatic, breast, gastric and colorectal cancer. We predict that blocking Trop2 and other regulatory signaling pathways will be an effective strategy to prevent disease progression in prostate and other human cancers.
Statement of Benefit to California: 
In 2012 alone in the state of California, an estimated 29,000 men will be diagnosed with prostate cancer and almost 3,400 men will die from the disease. The advanced stages of prostate cancer are treated with hormonal therapy which causes significant changes in mood, body weight and composition, impotence and gynecomastia in addition to the pain and suffering from the disease. Our proposed experiments will define new therapeutic targets and combinatorial therapies with the potential to significantly extend life and minimize suffering of men with advanced prostate cancer. Many of the molecules that we are investigating are implicated in a range of tumors, suggesting that our findings may provide benefit to patients suffering from numerous cancers.
Progress Report: 
  • Stem cells are characterized by longevity, self-renewal throughout the lifetime of a tissue or organism and the ability to generate all lineages of a tissue. Pathways involved in stem cell function are commonly dysregulated in cancer. Emerging evidence in leukemias and epithelial cancers suggests that tumors can be maintained by self-renewing cancer stem cells (CSCs), defined functionally by their ability to regenerate tumors. Delineating mechanisms that regulate self-renewal in human CSCs are essential to design new therapeutic strategies to combat cancer.
  • We have developed an in vivo tissue-regeneration model of primary human prostate cancer and identified two distinct populations of CSCs that can self-renew and serially propagate tumors. Both CSC subsets express the transmembrane protein Trop2. We have previously shown that Trop2 is a marker and a new regulator of stem/progenitor activity in the prostate. Trop2 controls self-renewal, proliferation and tissue hyperplasia through two cleavage products—intracellular domain (ICD) and extracellular domain (ECD) generated by regulated intramembrane proteolysis (RIP). RIP of Trop2 is carried out by TACE metalloprotease and gamma-secretase complex.
  • We have also demonstrated that cleaved Trop2 ICD is found in human prostate cancer but not in the cancer-adjacent benign tissue, suggesting a role for Trop2 cleavage in tumorigenesis. Now we are generating antibodies that will block Trop2 cleavage and activation. Blocking Trop2 signaling will be an effective strategy to prevent disease progression not only in the prostate but also in other epithelial cancers.
  • Stem cells are characterized by longevity, self-renewal throughout the lifetime of a tissue or organism and the ability to generate all lineages of a tissue. Pathways involved in stem cell function are commonly dysregulated in cancer. Emerging evidence in leukemias and epithelial cancers suggests that tumors can be maintained by self-renewing cancer stem cells (CSCs), defined functionally by their ability to regenerate tumors. Delineating mechanisms that regulate self-renewal in human CSCs are essential to design new therapeutic strategies to combat cancer.
  • We have developed an in vivo tissue-regeneration model of primary human prostate cancer and identified two distinct populations of CSCs that can self-renew and serially propagate tumors. Both CSC subsets express the transmembrane protein Trop2. We have previously shown that Trop2 is a marker and a new regulator of stem/progenitor activity in the prostate. Trop2 controls self-renewal, proliferation and tissue hyperplasia through two cleavage products—intracellular domain (ICD) and extracellular domain (ECD) generated by regulated intramembrane proteolysis (RIP). RIP of Trop2 is carried out by TACE metalloprotease and gamma-secretase complex.
  • We have also demonstrated that cleaved Trop2 ICD is found in human prostate cancer but not in the cancer-adjacent benign tissue, suggesting a role for Trop2 cleavage in tumorigenesis. So far we generated seventeen antibodies against Trop2. Currently we are testing the inhibitory effect of the antibodies on Trop2 cleavage and activation. Blocking Trop2 signaling will be an effective strategy to prevent disease progression not only in the prostate but also in other epithelial cancers.
Funding Type: 
Alpha Stem Cell Clinics
Grant Number: 
AC1-07659
Investigator: 
ICOC Funds Committed: 
$8 000 000
Disease Focus: 
Blood Disorders
Blood Cancer
Cancer
HIV/AIDS
Solid Tumor
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 
As the largest provider of bone marrow cell transplants in California, and the second largest in the nation, our institution has great expertise and an excellent record of safety in the delivery of stem cell treatments. We now propose to create the Alpha Clinic for Cell Therapy and Innovation (ACT-I) in which new, state-of-the-art, stem cell treatments for cancer and devastating blood-related diseases will be conducted and evaluated. As these experimental therapies prove to be effective, and become routine practice, our ACT-I Program will serve as the clinical center for delivery of these treatments. ACT-I will be an integral part of our Hematologic Malignancy and Stem Cell Transplantation Institute, placing it in the center of our institutional strengths, expertise, infrastructure and investment over the next decade. To move quickly once the CIRM award is made, ACT-I can be launched within our institution’s Day Hospital, a brand new, outpatient blood stem cell transplantation center opened in late 2013 with California Department of Health approval for 24 hour a day operation. This will ensure that ACT-I will have all the clinical and regulatory expertise, trained personnel, state-of-the-art facilities and other infrastructure in place to conduct first-in-human clinical trials and to deliver future, stem cell-based therapies for cancer and blood-related diseases, including AIDS. When our new Ambulatory Treatment Center is complete in 2018, it will double our capacity for patient visits and allow for expansion of the ACT-I pipeline of new stem cell products in a state-of-the-art facility. Beyond our campus, we operate satellite clinics covering an area that includes urban, suburban and rural sites. More than 17.7 million people live in this area, and represent some of the greatest racial and ethnic diversity seen in any part of the country. Our ACT-I is prepared to serve a significant, diverse and underserved portion of the population of California. CLINICAL TRIALS. Our proposal has two lead clinical trials that will be the first to be tested in ACT-I. One will deliver transplants of blood stem cells that have been modified to treat patients suffering from AIDS and lymphoma. The second will use neural stem cells to deliver drugs directly to cancer cells hiding in the brain. These studies represent some of the new and exciting biomedical technologies being developed at our institution. In addition to the two lead trials, we have several additional clinical studies poised to use and be tested in this special facility for clinical trials. In summary, ACT-I is well prepared to accommodate the long list of clinical trials and begin to fulfill the promise of providing new stem cell therapies for the citizens of California.
Statement of Benefit to California: 
California’s citizens voted for the California Stem Cell Research and Cures Act to support the development of stem cell-based therapies that treat incurable diseases and relieve human suffering. To achieve this goal, we propose to establish an Alpha Clinic for Cellular Therapies and Innovation (ACT-I) as an integral part of our Hematological Malignancies and Stem Cell Transplantation Institute, and serve as the clinical center for the testing and delivery of new, cutting-edge, cellular treatments for cancer and other blood-related diseases. Our institution is uniquely well-suited to serve as a national leader in the study and delivery of stem cell therapeutics because we are the largest provider of stem cell transplants in California, and the second largest in the country. According to national benchmarking data, our Hematopoietic Cell Transplantation program is the only program in the nation to have achieved survival outcomes above expectation for each of the past nine years. This program currently offers financially sustainable, research-driven clinical care for patients with cancer, HIV and other life-threatening diseases. CIRM funding will allow the ACT-I clinic to ramp up quickly, drawing upon institutionally established protocols, personnel and infrastructure to conduct first-in-human clinical trials for assessment of efficacy. As CIRM funding winds down, ACT-I will have institutional support to offer proven cellular therapeutics to patients. The lead studies at the forefront of the ACT-I pipeline of clinical trials focus on treatments for HIV-1 infection and brain tumors, two devastating and incurable conditions. These first trials are closely followed by a robust queue of other stem cell therapeutics for leukemia, lymphoma, prostate cancer, brain cancers and thalassemia. Our long list of proposed treatments addresses diseases that have a major impact on the lives of Californians. Thalassemia is found in up to 1 in 2,200 children born in California; prostate cancer affects 211,300 men, and HIV-1 infection occurs in 111,000 of our citizens. From 2008 to 2010, 6,705 Californians were diagnosed with brain cancers, 4,580 of whom died. In considering hematological malignancies during this same period, 2,800 patients were diagnosed with Hodgkin lymphoma (416 died), 20,351 with non-Hodgkin lymphoma (6,241 died), 13,358 with leukemia (6,961 died), 3,900 with acute myelogenous leukemia (2,972 died), 2,129 with acute lymphoblastic leukemia (648 died) and 4,198 with chronic lymphocytic leukemia (1,271 died). Standard of care fails in many cases; mortality rates for patients with hematological malignancies range from 25% to 76%. Successful stem cell therapeutics hold the promise to reduce disease-related mortality while improving disease-related survival and quality of life for the citizens of California, and for those affected by these diseases worldwide.
Funding Type: 
Basic Biology V
Grant Number: 
RB5-06978
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 161 000
Disease Focus: 
Solid Tumor
Cancer
Stem Cell Use: 
Cancer Stem Cell
oldStatus: 
Closed
Public Abstract: 
Tumors contain a heterogeneous mix of cancer cells with distinct features, including subsets of particularly aggressive stem-like cells. Since a single cancer stem cell can self-renew, divide, and differentiate to reconstitute the heterogeneity of an entire tumor, the ability of one cell to evade therapy or surgical resection could lead to tumor re-growth and disease relapse. Few, if any, individual markers have been capable of identifying cancer stem cells among distinct tumor types. It is therefore remarkable that we have detected enrichment of CD61 on stem-like cells within tumor biopsies from many different drug-resistant samples of lung, breast, pancreatic, and brain tumors from mice or humans. CD61 promotes a stem-like reprogramming event, since ectopic expression CD61 induces stemness, including self-renewal, tumor-forming ability, and resistance to therapy. CD61 drives these behaviors by activating a signaling pathway which can be inhibited to reverse stemness and sensitize tumors to therapy. Our project is focused on learning how CD61 drives this cancer stem cell program, and how the increase in CD61 could be prevented or reversed. If successful, our work will provide valuable new insight into a cancer stem cell program that is unexpectedly shared among a variety of solid tumor types.
Statement of Benefit to California: 
The American Cancer Society estimates 171,330 new cancer cases will be diagnosed in California this year, a 10th of the national total. As part of an NCI-designated comprehensive cancer, we are uniquely positioned to translate our basic science research into clinical impact for the cancer patients within our community. From a clinical perspective, the understanding gained from our proposed studies will broadly benefit patients in California who will be diagnosed with an epithelial cancer this year, including 25,360 new breast cancer patients and 18,720 new lung cancer patients. Gaining fundamental insight into how these cancers are reprogrammed to become more stem cell-like as they acquire resistance to therapy will facilitate development of new strategies to prevent or reverse this behavior to benefit these large numbers of patients who live in California. In addition, our work will also yield new diagnostic tools that could identify which patients might respond to certain therapies. At the basic science level, our project will also serve to elucidate the mechanisms by which cancer stem cells contribute to cancer progression and response to therapy. During the course of our project, we will be able to train more people in California to work on this cutting-edge research, and to establish a foundation for the logical design of anti-cancer therapies targeting this unique cancer stem cell population.
Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-07067
Investigator: 
Type: 
Co-PI
ICOC Funds Committed: 
$6 924 317
Disease Focus: 
Cancer
oldStatus: 
Active
Public Abstract: 
Cancer is a major cause of morbidity and mortality worldwide. Many believe that progress in drug development has not been as rapid as one would have predicted based on the significant technological advancements that have led to improved molecular understanding of this disease. There are numerous explanations for the lag in clinical success with new therapeutics. However, work in the past decade has provided support for what has become known as the cancer stem cell hypothesis. This model suggests that there is a class of cells that are the main drivers of tumor growth that are resistant to standard treatments. In one model the cancer stem cells inhabit an anatomical “niche” that prevents drug efficacy. Another view is one in which tumors can achieve resistance by cell fate decisions in which some tumor cells are killed by therapeutics, while other cells avoid this fate by choosing to become cancer stem cells. These stem cells are thought to be capable of both cancer stem cell renewal and repopulation of the tumor. Our proposal aims to conduct a Phase I clinical trial of a first-in-class mitotic inhibitor. The target is a serine/threonine kinase that was originally selected because blocking this target affects both tumor cell lines and tumor initiating cells (TICs). Our data suggest that the target kinase functions at the intersection of mitotic regulation, DNA damage and repair, and cell fate decisions associated with stem cell renewal. Preclinical work has begun to segregate “sensitive” and “resistant” groups of tumor cell lines and TICs after treatment with the drug candidate as a single agent and in combination with standard-of-care therapeutics. Our data also support the model in which cancer stem cell resistance is likely to arise, at least in some cases, due to stem cell fate decisions that happen in response to therapeutic intervention. This grant is a natural progression of work partially funded by CIRM that enabled the isolation of Tumor Initiating Cells (TICs)from tumors in different tissue types. This facilitated the development and assessment of drug candidates that target both bulk tumor cells and TICs and has now led to the development of a potential anti-cancer drug which we are now preparing to test in humans. The goal of the Phase I trial is to determine the maximum tolerated dose, the recommended Phase II dose, and any dose-limiting toxicities. We will also characterize safety, pharmacokinetic, and pharmacodynamic profiles along with any antitumor activity. Once the maximum tolerated dose has been identified, a biomarker expansion cohort will be opened in order to determine whether appropriately selected biomarkers are associated with a predictable patient response. This will allow a rational approach to study single agent and combination studies that perturb this network and allow us the opportunity to facilitate a targeted clinical development plan.
Statement of Benefit to California: 
It has been estimated, by the California Department of Public Health, that in 2013 about 145,000 Californians will be diagnosed with cancer and more than 55,000 of these will ultimately succumb to their disease. Furthermore, more than 1.3 million Californians are living today with a history of cancer. Therefore, innovative research programs that are able to impact this devastating disease burden are likely to have a large potential benefit to the state of California and its residents. This grant application proposes a Phase I clinical trial for a first-in-class inhibitor of a target that has never been tested in patients. The aim of this trial is to determine the maximum tolerated dose in humans, the recommended dose for phase II trials, and evaluate any dose-limiting toxicities. The trial will also characterize safety, pharmacokinetics, and pharmacodynamic properties. It will also provide early insight into any antitumor activity. Our group has developed a comprehensive unbiased platform that facilitates the segregation of sensitive and resistant populations of cancer based on their molecular subtypes. This capability has the promise to improve the success rate and reduce the cost of oncology clinical trials by focusing on the subsets that are most likely to benefit while avoiding unnecessarily treating patients that would otherwise benefit from alternative treatments. Our preliminary pre-clinical work, funded by CIRM in the context of a Disease Team I award, suggests that this approach can be successfully applied to the networks associated with mitotic regulation, DNA repair, and stem-cell fate decisions. Our ongoing research has tested a number of chemical compounds that are able to block pathways that are critical to the growth and proliferation of many cancer models. These compounds have all been tested in multiple in vitro and in vivo systems and have been found to inhibit the ability of the cancer stem cell to repopulate. Now that our pre-clinical enabling studies have been completed, we have submitted an Investigational New Drug (IND) application to the FDA for a first-in-human phase I clinical trial. In the current proposal, we will be able to test our hypotheses in a clinical setting, which if successful will lead to confirmation of safety and the establishment of the appropriate dose with which to test in later stage trials. This trial will set the stage for a new class of agents that has not yet been tested in clinical settings. We believe that the proposal described herein has the promise to expand the reach of targeted therapies into mechanisms that in most cases have been resistant to innovation. Finally, it is reasonable to expect that our preclinical work and the proposed clinical trials will validate a number of potential biomarkers that will identify susceptible patient subpopulations.
Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-06924
Investigator: 
Type: 
PI
Type: 
Co-PI
ICOC Funds Committed: 
$4 179 600
Disease Focus: 
Blood Cancer
Cancer
oldStatus: 
Active
Public Abstract: 
Cancer is a leading cause of death in California. Research has found that many cancers can spread throughout the body and resist current anti-cancer therapies because of cancer stem cells, or CSC. CSC can be considered the seeds of cancer; they can resist being killed by anti-cancer drugs and can lay dormant, sometimes for long periods, before growing into active cancers at the original tumor site, or at distant sites throughout the body. Required are therapies that can kill CSC while not harming normal stem cells, which are needed for making blood and other cells that must be replenished. We have discovered a protein on the surface of CSC that is not present on normal cells of healthy adults. This protein, called ROR1, ordinarily is found only on cells during early development in the embryo. CSC have co-opted the use of ROR1 to promote their survival, proliferation, and spread throughout the body. We have developed a monoclonal antibody that is specific for ROR1 and that can inhibit these functions, which are vital for CSC. Because this antibody does not bind to normal cells, it can serve as the “magic bullet” to deliver a specific hit to CSC. We will conduct clinical trials with the antibody, first in patients with chronic lymphocytic leukemia to define the safety and best dose to use. Then we plan to conduct clinical trials involving patients with other types of cancer. To prepare for such clinical trials, we will use our state-of-the-art model systems to investigate the best way to eradicate CSC of other intractable leukemias and solid tumors. Finally, we will investigate the potential for using this antibody to deliver toxins selectively to CSC. This selective delivery could be very active in killing CSC without harming normal cells in the body because they lack expression of ROR1. With this antibody we can develop curative stem-cell-directed therapy for patients with any one of many different types of currently intractable cancers.
Statement of Benefit to California: 
The proposal aims to develop a novel anti-cancer-stem-cell (CSC) targeted therapy for patients with intractable malignancies. This therapy involves use of a fully humanized monoclonal antibody specific for a newly identified, CSC antigen called ROR1. This antibody was developed under the auspices of a CIRM disease team I award and is being readied for phase I clinical testing involving patients with chronic lymphocytic leukemia (CLL). Our research has revealed that the antibody specifically reacts with CSC of other leukemias and many solid-tumor cancers, but does not bind to normal adult tissues. Moreover, it has functional activity in blocking the growth and survival of CSC, making it ideal for directing therapy intended to eradicate CSC of many different cancer types, without affecting normal adult stem cells or other normal tissues. As such, treatment could avoid the devastating physical and financial adverse effects associated with many standard anti-cancer therapies. Also, because this therapy attacks the CSC, it might prove to be a curative treatment for California patients with any one of a variety different types of currently intractable cancers. Beyond the significant benefit to the patients and families that are dealing with cancer, this project will also strengthen the position of the California Institute of Regenerative Medicine as a leader in cancer stem cell biology, and will deliver intellectual property to the state of California that may then be licensed to pharmaceutical companies. In summary, the benefits to the citizens of California from the CIRM disease team 3 grant are: (1) Direct benefit to the thousands of patients with cancer (2) Financial savings through definitive treatment that obviates costly maintenance or salvage therapies for patients with intractable cancers (3) Potential for an anti-cancer therapy with a high therapeutic index (4) Intellectual property of a broadly active uniquely targeted anti-CSC therapeutic agent.

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