CANCER FIGHTERS 2020 AWARDEE
DEVELOPING NEW STRATEGIES TO PREVENT AND TREAT MELANOMA METASTASES
Michael A. Davies, MD, PhD, University of Texas MD Anderson Cancer Center
Brain metastases are a devastating and increasingly common complication of advanced cancer. For example, previous studies have shown that up to 60% of patients with metastatic melanoma, the most aggressive form of skin cancer, will be diagnosed with brain metastases during the course of their disease. Historically the average survival for melanoma patients with brain metastases was very short. However, recent, clinical trials with new immune and targeted therapies have demonstrated much more promising results. Despite these advances, most patients still fail to achieve durable control of brain metastases, and brain metastases remain a leading cause of morbidity and mortality in this disease. Thus, developing more effective strategies to prevent and treat brain metastases from melanoma remains a critical unmet need. |
The efficient development more effective treatments for brain metastases depends upon improving our understanding of the features that promote and sustain these tumors. Recently our lab conducted the first global analysis of the molecular features of melanoma brain metastases.Specifically, our studies showed that melanoma brain metastases upregulate oxidative phosphorylation, a metabolic pathway that generates energy and key molecules for cancer cell growth. Importantly, our studies also showed that the tumor depend upon this pathway, as a small molecule inhibitor of oxidative phosphorylation prolonged the survival of mice with melanoma brain metastases. These studies have shed new light on these tumors, and have identified aberrant tumor metabolism as a new player and therapeutic target in this disease.
This proposal will build upon these initial findings to support the development of new strategies to prevent and treat brain metastases from melanoma. First, we will determine if metabolic features of tumors can help to predict which melanoma patients are most likely to develop brain metastases. Developing an improved understanding of the factors that predict risk of brain metastasis could have clinical impact through the development of evidence-based strategies for increased screening for high-risk patients. The identification of molecular or immune factors that correlate with increased risk of brain metastasis may also suggest rational strategies to decrease their development. Second, we will evaluate the efficacy and metabolic effects of different strategies to inhibit oxidative phosphorylation in melanoma brain metastases. While our initial experiments with a direct inhibitor of oxidative phosphorylation confirmed the importance of this pathway, the drug used in those experiments can cause significant side effects. Fortunately, studies by our group and others have identified additional strategies that can inhibit oxidative phosphorylation in cancer cells which may be safer. We will test if these new approaches are able to inhibit oxidative phosphorylation in melanoma brain metastases, if they can inhibit the growth of these tumors, and if they can help to overcome resistance to approved immune and targeted therapies for this disease.
Together these experiments will help accelerate our research to prevent and control brain metastases from melanoma. Importantly, our recent experiments suggest that some processes that promote the development and aggressiveness of brain metastases from melanoma may also play a role in brain metastases from other cancers as well, thus expanding the potential impact of these studies. We also plan to leverage this generous donation toward the development of future funding applications, to further amplify the impact of this support.
This proposal will build upon these initial findings to support the development of new strategies to prevent and treat brain metastases from melanoma. First, we will determine if metabolic features of tumors can help to predict which melanoma patients are most likely to develop brain metastases. Developing an improved understanding of the factors that predict risk of brain metastasis could have clinical impact through the development of evidence-based strategies for increased screening for high-risk patients. The identification of molecular or immune factors that correlate with increased risk of brain metastasis may also suggest rational strategies to decrease their development. Second, we will evaluate the efficacy and metabolic effects of different strategies to inhibit oxidative phosphorylation in melanoma brain metastases. While our initial experiments with a direct inhibitor of oxidative phosphorylation confirmed the importance of this pathway, the drug used in those experiments can cause significant side effects. Fortunately, studies by our group and others have identified additional strategies that can inhibit oxidative phosphorylation in cancer cells which may be safer. We will test if these new approaches are able to inhibit oxidative phosphorylation in melanoma brain metastases, if they can inhibit the growth of these tumors, and if they can help to overcome resistance to approved immune and targeted therapies for this disease.
Together these experiments will help accelerate our research to prevent and control brain metastases from melanoma. Importantly, our recent experiments suggest that some processes that promote the development and aggressiveness of brain metastases from melanoma may also play a role in brain metastases from other cancers as well, thus expanding the potential impact of these studies. We also plan to leverage this generous donation toward the development of future funding applications, to further amplify the impact of this support.
CANCER FIGHTERS 2019 AWARDEE
DEPARTMENT OF GASTROENTEROLOGY HEPATOLOGY AND NUTRITION, DIVISION OF INTERNAL MEDICINE
CANCER FIGHTERS 2018 AWARDEE
TEXAS A&M INSTITUTE OF BIOSCIENCES AND TECHNOLOGY
In summary, my expertise and experience have prepared me well to successfully lead and execute the proposed studies with the ultimate goal of revealing novel pathogenic mechanisms underlying different cancer types, especially pediatric brain tumors. The proposed research will utilize my experience in working with cancer stem cells, epigenetic profiling, biochemistry, and transgenic mice generation and characterization.
Target Cancer population. Brain tumor is the leading cause of cancer related death in children and accounts for ~20% of all types of pediatric cancers. Radiation is the standard therapy for nearly all the pediatric malignant brain tumors, but the survivors are often left with long term cognitive or neurological disorders due to permanent damage to the brain. Despite initial responses, many brain tumors relapse and often lead to a harder-to-treat cancer phenotype. This is particularly true in children with glioblastomas (GBM), medulloblastoma, and ependymoma. One of the major culprits for resistance to radiotherapies is tumor stem cells, a small subpopulation of tumor cells that often survive the initial anti-cancer therapies. These cells are the seed cells driving tumor initiation and progression which are usually quiescent for longer intervals and then reactivated to cause treatment resistance and tumor relapse. Clearly, there is a pressing need for the discovery of tumor stem cellspecific features in patients, as well as for the development of more effective antitumor drugs that specifically target tumor stem cells.
Intervention proposed. (i) From clinic to bench: We will use our established panels of PDOX mice models to unveil the epigenetic landscapes in tumor stem cells, with the objective of identifying key epigenetic elements that are closely involved in therapy resistance during the treatment of pediatric brain cancers. Pediatric brain cancers can come back after a standard radiation therapy. Standard radiotherapies are mostly directed against the bulk of brain cancer cells, but spare the cancer stem cells, which will survive the anti-cancer therapy and re-establish a harder-to-treat cancer phenotype. Cancer stem cells often have distinct epigenetic signatures and remain quiescent for longer intervals during treatment and then relapse. (ii) From bench to therapeutic development: We will use a set of small molecules that have been identified to target epigenetic pathways to induce brain tumor stem cell differentiation, and rigorously test if this strategy will enhance radiation-induced cancer cell killing.
In summary, funds received from Cancer Fighter will be used to discover novel epigenetic marks that are involved in switching brain tumor cells from a hard-to-kill stem-like status to a more susceptible differentiated status. The feasibility of our approach is best attested by the identification of several key epigenetic regulators that show significant difference between tumor stem cell and differentiated tumor cells in glioblastomas. It is our future plan to extend our analysis to other types of epigenetic marks in various brain tumors to benefit child patients suffering from brain cancer.
Target Cancer population. Brain tumor is the leading cause of cancer related death in children and accounts for ~20% of all types of pediatric cancers. Radiation is the standard therapy for nearly all the pediatric malignant brain tumors, but the survivors are often left with long term cognitive or neurological disorders due to permanent damage to the brain. Despite initial responses, many brain tumors relapse and often lead to a harder-to-treat cancer phenotype. This is particularly true in children with glioblastomas (GBM), medulloblastoma, and ependymoma. One of the major culprits for resistance to radiotherapies is tumor stem cells, a small subpopulation of tumor cells that often survive the initial anti-cancer therapies. These cells are the seed cells driving tumor initiation and progression which are usually quiescent for longer intervals and then reactivated to cause treatment resistance and tumor relapse. Clearly, there is a pressing need for the discovery of tumor stem cellspecific features in patients, as well as for the development of more effective antitumor drugs that specifically target tumor stem cells.
Intervention proposed. (i) From clinic to bench: We will use our established panels of PDOX mice models to unveil the epigenetic landscapes in tumor stem cells, with the objective of identifying key epigenetic elements that are closely involved in therapy resistance during the treatment of pediatric brain cancers. Pediatric brain cancers can come back after a standard radiation therapy. Standard radiotherapies are mostly directed against the bulk of brain cancer cells, but spare the cancer stem cells, which will survive the anti-cancer therapy and re-establish a harder-to-treat cancer phenotype. Cancer stem cells often have distinct epigenetic signatures and remain quiescent for longer intervals during treatment and then relapse. (ii) From bench to therapeutic development: We will use a set of small molecules that have been identified to target epigenetic pathways to induce brain tumor stem cell differentiation, and rigorously test if this strategy will enhance radiation-induced cancer cell killing.
In summary, funds received from Cancer Fighter will be used to discover novel epigenetic marks that are involved in switching brain tumor cells from a hard-to-kill stem-like status to a more susceptible differentiated status. The feasibility of our approach is best attested by the identification of several key epigenetic regulators that show significant difference between tumor stem cell and differentiated tumor cells in glioblastomas. It is our future plan to extend our analysis to other types of epigenetic marks in various brain tumors to benefit child patients suffering from brain cancer.
CANCER FIGHTERS 2017 AWARDEE
Samir "Sam" M. Hanash, MD, PhD
Dr. Hanash, professor of Clinical Cancer Prevention, was recruited to The University of Texas MD Anderson Cancer Center in July 2012 to lead the Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer as director. He is a pioneer in cancer proteomics, a field aimed at identifying, among thousands of proteins, those that inform about cancer. He was the inaugural president of the Human Proteome Organization (HUPO) and a founder of the US Human Proteome Organization. In 2006, Nature Biotechnology listed Dr. Hanash among the world’s most influential leaders in biotechnology for his work in cancer proteomics. He is a former program head for molecular diagnostics at the Fred Hutchinson Cancer Research Center in Seattle. Prior to this, he rose through the ranks at the University of Michigan, where he earned his Ph.D. in human genetics and later became the Henry Sewall Endowed Professor. Dr. Hanash’s transformational work on cancer biomarkers delivers on the long-held concept that cells express disease-indicator proteins well before symptoms appear. |
As early as 1988, he reported on cancer markers for acute lymphoblastic leukemia and cellular peptides that distinguish cancer in infants and in older children. Searching for those almost imperceptible, yet very telling cellular expressions has been an essential theme in his early cancer detection work — inspired and stimulated by his experience as a clinician treating patients with advanced-stage disease and dim prospects for cure.
In 2001, he began a large-scale, National Cancer Institute-funded project to molecularly classify tumors and develop blood-based biomarkers using integrated genomic and proteomic approaches. This work provided proof of principal for the use of proteomics to develop cancer biomarkers. The next year, he discovered a signature of gene-expression profiles that could predict the survival of patients with early-stage lung adenocarcinoma. And through HUPO, he initiated a collaborative study that involved 35 laboratories and harnessed plasma proteome profiling and tumor and proteome profiling to develop promising panels for early detection of lung and other cancers.
Dr. Hanash’s dedication to developing markers that signal cancer at an early, curable stage has included painstaking, in-depth profiling of the thousands of circulating proteins in the blood to find those that are released early, either from cancer cells or as a host response to the developing cancer. He emphasizes the need for rigor in experimental design, data collection and statistical analysis,
and in developing a mechanistic understanding of the relationship between identified cancer markers and the developing cancer. This has sparked innovation in statistical analysis of proteomic data aimed at minimizing biases in discovery studies through prospective sample collections that relate most directly to intended clinical application(s), and at reducing the false-discovery rate by integrating data from multiple sources to increase confidence in the markers’ significance.
In 2001, he began a large-scale, National Cancer Institute-funded project to molecularly classify tumors and develop blood-based biomarkers using integrated genomic and proteomic approaches. This work provided proof of principal for the use of proteomics to develop cancer biomarkers. The next year, he discovered a signature of gene-expression profiles that could predict the survival of patients with early-stage lung adenocarcinoma. And through HUPO, he initiated a collaborative study that involved 35 laboratories and harnessed plasma proteome profiling and tumor and proteome profiling to develop promising panels for early detection of lung and other cancers.
Dr. Hanash’s dedication to developing markers that signal cancer at an early, curable stage has included painstaking, in-depth profiling of the thousands of circulating proteins in the blood to find those that are released early, either from cancer cells or as a host response to the developing cancer. He emphasizes the need for rigor in experimental design, data collection and statistical analysis,
and in developing a mechanistic understanding of the relationship between identified cancer markers and the developing cancer. This has sparked innovation in statistical analysis of proteomic data aimed at minimizing biases in discovery studies through prospective sample collections that relate most directly to intended clinical application(s), and at reducing the false-discovery rate by integrating data from multiple sources to increase confidence in the markers’ significance.
MD ANDERSON CANCER CENTER
CANCER FIGHTERS 2016 AWARDEE
Stephanie A Pangas, Ph.D.
PROFESSIONAL STATEMENT Twenty percent of women’s health problems worldwide are attributed to reproductive and sexual health issues. Disruptions in normal reproductive function cause health problems that extend beyond infertility, and include increases in cardiovascular disease, osteoporosis, and cognitive disorders. Furthermore, ovarian cancer is the most lethal gynecologic malignancy in women. In part, this is due to a lack of diagnostics needed for early detection. Therefore, the origin, diagnosis, and treatment of gynecological diseases are critical health issues that need to be addressed. |
Our research laboratory focuses on understanding how the ovary normally develops and functions, and how defects in these processes result in reproductive disorders and cancer development. We use a multifaceted approach, generating data from patient samples, immortalized cancer cell lines, and genetically modified mice. Since the laboratory has started in 2007, our research has contributed a number of key mouse models for genes that cause infertility, ovarian dysfunction, and ovarian cancer. These models are paramount in the search for novel therapeutics and diagnostics for patients with reproductive diseases.
BAYLOR COLLEGE OF MEDICINE
CANCER FIGHTERS 2015 AWARDEE
Steven A. Curley, M.D
Dr. Steven A. Curley specializes in providing surgical care for patients with hepatobiliary and pancreatic malignancies. As our chief of surgical oncology and cancer center associate director, he leads efforts at Baylor College of Medicine (BCM) and on the McNair campus to build a world-class, multidisciplinary surgical oncology program with significant national and international outreach and stature. Dr. Curley has been leading a basic sciences laboratory for 22 years. Currently, his research centers on the design, bench testing, and clinical study of novel noninvasive radiofrequency (RF) field treatment devices. Having developed two FDA-approved devices for invasive radiofrequency ablation needles to treat unresectable liver cancers, his current studies focus on targeted delivery of metallic or semiconducting nanoparticles that release heat under RF field induction to cause thermal cytotoxicity in cancer cells. His group has also performed complex physicochemical measurements of nanoparticles, and has conjugated them to antibodies, peptides, and pharmacologic agents to target cancer cells. He hopes to test these novel treatments in human clinical trials at BCM within the next two to three years, pending FDA approval. |
WWW.BCM.EDU
CANCER FIGHTERS 2014 AWARDEE
Brendan Lee, M.D., Ph.D.
Dr. Lee is Professor of Molecular & Human Genetics, Baylor College of Medicine Howard Hughes Medical Institute Investigator Director of the Rolanette and Berdon Lawrence Bone Disease Program of Texas. He is also founder and director of the Skeletal Dysplasia Clinic at Texas Children’s Hospital and founder and director of the Medical Student Research Track at Baylor College of Medicine. |
As a pediatrician and geneticist, Dr. Lee studies structural birth defects and inborn errors of metabolism. Dr. Lee identified the first genetic causes of human skeletal dysplasias, birth defects that affect either the growth or strength of the skeleton. Most recently, he has studied the causes of brittle bone disease in children. In so doing, he is developing new approaches for diagnosing and treating these disorders. These conditions may present with hundreds of fractures at birth or isolated osteoporosis in children. The treatments have helped children who were destined to be wheelchair bound because of bony fractures and deformities to now be able to walk and run in everyday life activities. As part of his work in metabolic disorders, he is developing new treatments for diseases like maple syrup urine disease and urea cycle disorders that are now identified very early because of comprehensive newborn screening. Because these potentially devastating diseases are now being diagnosed even before children have symptoms, it is essential that effective treatment approaches are in place to prevent future complications that may lead to brain injury and death. To do so, Dr. Lee has developed and led both National Institute of Health and Industry funded clinical trials to test new treatments in these disorders.
Dr. Lee has received local and national recognition including induction into the American Association of Physicians, the American Society for Clinical Investigation, the Texas Academy of Medicine, Science, and Technology Edith and Peter O’Donnell Award in Medicine, the E. Meade Johnson Award for Pediatrics Research, the Michael E. DeBakey Excellence in Research Award, and the American Philosophical Society’s Judson Darland Prize for Patient-Oriented Clinical Investigation.
Dr. Lee has received local and national recognition including induction into the American Association of Physicians, the American Society for Clinical Investigation, the Texas Academy of Medicine, Science, and Technology Edith and Peter O’Donnell Award in Medicine, the E. Meade Johnson Award for Pediatrics Research, the Michael E. DeBakey Excellence in Research Award, and the American Philosophical Society’s Judson Darland Prize for Patient-Oriented Clinical Investigation.
MD Anderson Seed Grants
2007 Dr. Nicholas Vauthey - Dr. Vauthey’s grant was for $14,500. His findings were published in the Dec 4 issue of JAMA (Chun et al) and a paper by Blazer et al published in Journal of Clinical Oncology. Two of his fellows who worked on these papers were funded in part by Cancer Fighters of Houston. The information collected has directly influence patient treatment for colorectal cancer and decrease negative side effects and resulted in a pharmaceutical company grant of $200,000 which will fund the salary for 2 more research fellows.
2006 Dr. Patrick Hwu - States that many of our current treatments boosting the patients own immune system against multiple melanoma are the direct results of his teams’ research efforts and were initially funded by private donor sources included is $20,000 from Cancer Fighters. Please know that Cancer Fighters’ gift was put to excellent use, and may ultimately affect the lives of numerous patients and their families. Under these strained economic conditions, our support has allowed us to maintain forward momentum. Your investment in our program means a great deal to me, my faculty, and staff and has lead to larger funding of $8.6 million and several publications.
2006 Dr. Jeffrey Tarrand - Received $20,000 from Cancer Fighters to support the development of an innovative virus to kill pancreatic cancer.He used our funding to test the virus for negative side effects in a large animal study. With his excellent results he has now set up new lab specifically to develop the Reovirus and test it on mice with Leukemia and Pancreatic cancer.
Baylor College of Medicine Seed Grants
Dr. Xiao-Nan Li 2007 - Cancer Fighters helped him finalize an animal model that allowed him to do his research on brain cancer in children. Cancer Fighters awarded him $20,000. Has received 2 grants as the lead investigator and received 2 additional grants as a co-investigator. He is involved in 5 collaborative research projects using the mouse model with colleagues at Johns Hopkins University, Duke, Pittsburgh, U of Michigan, Wash U in Seattle, and one United Kingdom collaborative. He has published his results in the journal of STEM CELLS and gives Cancer Fighters acknowledgement for our funding.
Mike Lewis PhD 2008 - Dr. Lewis’ team was awarded $50,000 from Cancer Fighters to address treatment in late stage resistant breast cancers. Twelve papers were published in last year and 6 are in progress. The Breast Center at Baylor College of Medicine just received a treatment grant from the federal agency for $11.5 million which will be in collaboration with Methodist Hospital.
Ching Lau, MD, PhD 2004-2005 - Cancer Fighters awarded two $45,000 awards to Dr. Lau. As a result of his research efforts he has received 9 major grants totalling about $7.2 million. Two papers, one on bone tumor and the other one on brain tumor were published. The Cancer Fighters' name is found in the acknowledgement section at the end of the papers.
Methodist Hospital Seed Grant
2008 Dr. Brian Butler - Drs. Brian E. Butler and John E. McGary at The Methodist Hospital have identified two types of sensors—superconducting quantum device magnetometers (SQUID) and Magnetoresistive (MR) a project recently funded by Cancer Fighters of Houston for $40,000. They found that both types of sensors have drawbacks that currently limit their effectiveness as affordable and reliable devices for tracking tumors in real-time. Drs. Butler and McGary now have a better understanding of localization accuracy, however, and are continuing to refine their research. I am excited to report that this project has already been accepted for publication in two journals:International Journal of Radiation Oncology*Biology*Physics and IEEE Transactions on Magnetics.
2007 Dr. Nicholas Vauthey - Dr. Vauthey’s grant was for $14,500. His findings were published in the Dec 4 issue of JAMA (Chun et al) and a paper by Blazer et al published in Journal of Clinical Oncology. Two of his fellows who worked on these papers were funded in part by Cancer Fighters of Houston. The information collected has directly influence patient treatment for colorectal cancer and decrease negative side effects and resulted in a pharmaceutical company grant of $200,000 which will fund the salary for 2 more research fellows.
2006 Dr. Patrick Hwu - States that many of our current treatments boosting the patients own immune system against multiple melanoma are the direct results of his teams’ research efforts and were initially funded by private donor sources included is $20,000 from Cancer Fighters. Please know that Cancer Fighters’ gift was put to excellent use, and may ultimately affect the lives of numerous patients and their families. Under these strained economic conditions, our support has allowed us to maintain forward momentum. Your investment in our program means a great deal to me, my faculty, and staff and has lead to larger funding of $8.6 million and several publications.
2006 Dr. Jeffrey Tarrand - Received $20,000 from Cancer Fighters to support the development of an innovative virus to kill pancreatic cancer.He used our funding to test the virus for negative side effects in a large animal study. With his excellent results he has now set up new lab specifically to develop the Reovirus and test it on mice with Leukemia and Pancreatic cancer.
Baylor College of Medicine Seed Grants
Dr. Xiao-Nan Li 2007 - Cancer Fighters helped him finalize an animal model that allowed him to do his research on brain cancer in children. Cancer Fighters awarded him $20,000. Has received 2 grants as the lead investigator and received 2 additional grants as a co-investigator. He is involved in 5 collaborative research projects using the mouse model with colleagues at Johns Hopkins University, Duke, Pittsburgh, U of Michigan, Wash U in Seattle, and one United Kingdom collaborative. He has published his results in the journal of STEM CELLS and gives Cancer Fighters acknowledgement for our funding.
Mike Lewis PhD 2008 - Dr. Lewis’ team was awarded $50,000 from Cancer Fighters to address treatment in late stage resistant breast cancers. Twelve papers were published in last year and 6 are in progress. The Breast Center at Baylor College of Medicine just received a treatment grant from the federal agency for $11.5 million which will be in collaboration with Methodist Hospital.
Ching Lau, MD, PhD 2004-2005 - Cancer Fighters awarded two $45,000 awards to Dr. Lau. As a result of his research efforts he has received 9 major grants totalling about $7.2 million. Two papers, one on bone tumor and the other one on brain tumor were published. The Cancer Fighters' name is found in the acknowledgement section at the end of the papers.
Methodist Hospital Seed Grant
2008 Dr. Brian Butler - Drs. Brian E. Butler and John E. McGary at The Methodist Hospital have identified two types of sensors—superconducting quantum device magnetometers (SQUID) and Magnetoresistive (MR) a project recently funded by Cancer Fighters of Houston for $40,000. They found that both types of sensors have drawbacks that currently limit their effectiveness as affordable and reliable devices for tracking tumors in real-time. Drs. Butler and McGary now have a better understanding of localization accuracy, however, and are continuing to refine their research. I am excited to report that this project has already been accepted for publication in two journals:International Journal of Radiation Oncology*Biology*Physics and IEEE Transactions on Magnetics.