Creativity Award Recipients 2010
About Creativity Award Recipients 2010
The Gordon Becker Creativity Award
Gustavo Ayala, MD – Baylor College of Medicine, Texas
Targeting Neurogenesis in Prostate Cancer
The prostate gland is rich in nerves and proteins that support nerve growth (neural growth factors). Studies from Dr. Ayala’s group have demonstrated that prostate cancer cells directly interact with nerves. The data also showed that nerve density in the prostate was highest in areas with cancer. Based on these observations, Dr. Ayala hypothesized that neurogenesis (nerve growth) permits and/or promotes prostate cancer progression. To test this, Dr. Ayala and colleagues have designed a first-in-man clinical trial testing a powerful neurotoxin, Botulinum Neurotoxin Type A (BoNT-A) also known as BOTOX, that blocks nerve activity and growth. This study will determine whether interruption of neurogenesis with BoNT-A activates anti-tumor activity and will identify the tumor-promoting mechanism underlying the interaction between nerve cells and prostate cancer cells.
Brendan Curti, MD – Providence Portland Medical Center, Oregon
Augmenting OX40 Immunotherapy in Men with Advanced Prostate Cancer
Dr. Curti and his team are pioneers in the preclinical and clinical development of a new immunotherapy that activates the anti-tumor effects of patients’ own T cells (a type of white blood immune cell). This new target, OX40, is a cell surface molecule on T cells that when properly activated can induce T cells to kill cancer cells. A Phase I Clinical Trial showed that prostate cancer patients treated with a monoclonal antibody directed against OX-40 (anti-OX40) had the greatest increase in the frequency of anti-tumor T cells relative to other solid tumor patients. Additionally, pre-clinical studies in mouse models revealed that anti-OX40 in combination with chemotherapy and radiation had the greatest anti-cancer effect. This project will extend these findings into the clinic by initiating a clinical investigation to evaluate anti-OX40 in combination with chemotherapy and radiation therapy in patients with metastatic prostate cancer. During the study, the investigators will be monitoring the frequency of T cells in patients undergoing treatment to identify whether T cell quantification can predict clinical response to this treatment strategy. Anti-OX40 is first-in-man, first in prostate cancer. This work promises to enhance effectiveness of immunotherapy.
Jennifer Doll, PhD – NorthShore University HealthSystem Research Institute, Illinois
Periprostatic Fat as a Promoter of Prostate Cancer Progression
Obesity and high fat diets are associated with more aggressive prostate cancer. Yet, the mechanism underlying this association remains unclear. Dr. Doll and colleagues hypothesize that periprostatic fat (fat adjacent to the prostate) from obese patients has an enhanced capacity to promote prostate cancer growth by increasing the level of triglycerides and fatty acids within cancer cells. Fatty acids and triglycerides have been shown to promote prostate cancer cell growth in vitro and analysis of obese patient tumor specimens revealed that many cancer cells contained fat droplets. In her proposal she plans to identify how fatty acids and triglycerides released from periprostatic fat promote prostate tumor growth and whether levels of fatty acid and triglycerides in the periprostatic fat correlate with clinical outcome. Early data from Dr. Doll’s work reveal that fat may block the production of an important protein called, PEDF. PEDF suppresses fatty acid and triglyceride accumulation and blocks new vessel growth called angiogenesis in the tumor. This study may identify new therapeutic targets, such as PEDF, for the treatment of advanced prostate cancer.
The Evensen Family – PCF Creativity Award
Charles Drake, MD, PhD – Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Maryland
Combining PD-1 Mediated Checkpoint Blockade with Active Immunotherapy for Prostate Cancer: A Neoadjuvant Trial
The immune system is capable of identifying cancer cells as foreign and causing their destruction. This decades-old theory is called immune surveillance. However, in many patients, including men with prostate cancer, the immune system becomes fatigued and can no longer prevent cancer progression. PD-1 is a cell surface protein that is expressed on exhausted immune cells and impairs an anti-tumor immune response. Dr. Drake has designed a comprehensive study to assess the clinical value of combining immunotherapy (a cancer vaccine) with an inhibitor of PD-1 to enhance a patient’s immune response against advanced prostate cancer. Blockade of PD-1 releases the brakes on the immune response, revitalizing the body’s ability to kill cancer cells. Anti-PD1 is in first-in-man clinical testing. This project could enhance the efficacy of immunotherapy treatments in men with advanced prostate cancer.
James Marshall, PhD – Roswell Park Cancer Institute, New York
Diet and Progression of Prostate Cancer among Men on Active Surveillance
Active surveillance is a clinical program for men diagnosed with very early (low grade and stage) prostate cancer who decide with their physician to delay treatment. The challenge during active surveillance is to prevent disease progression and the subsequent need for local therapy. Extensive epidemiological studies suggest that metabolic changes from a calorie-controlled diet high in fruits and vegetables are associated with reduction in risk for prostate cancer progression. Dr. Marshall proposes to test these observations in a clinical study called Men’s Eating and Living (MEAL) study, a rigorous dietary intervention. Men will change their diet to the following: 7 servings per day of vegetables (2 cruciferous, 2 tomato products, 3 other vegetables), 2 servings per day of whole grains, 1 serving per day of beans or other legumes, and 2 servings per day of fruit. Over a 2 year period, study participants will be closely monitored for metabolic changes by measuring the chemical byproducts released from cells into circulation. The results from this study will define the impact of a dietary intervention on delaying surgical or radiation treatment in this subset of patients. The study will also identify molecular correlates of dietary change which may provide insight into novel prostate cancer therapeutics and/or cancer prevention strategies.
Nora Navone, MD, PhD – The University of Texas MD Anderson Cancer Center
FGFR Inhibition to Develop Effective Combination Therapies
Fibroblast growth factor (FGF) and its receptor (FGFR) form a protein-protein complex that has been implicated in prostate tumor cells as a pathway that drives prostate cancer progression and metastasis. FGF signaling causes blood vessel growth within the tumor through a process called angiogenesis. This process provides the growing tumor with nourishing blood and drives tumor cell growth. Dr. Navone and colleagues have initiated a first-in-man clinical study to assess the effectiveness of a novel agent called TKI258, an inhibitor of FGF signaling. The study includes a comprehensive molecular profiling of patient tissue obtained from metastatic sites. Results will inform how prostate cancer cells respond to TKI258 at the molecular level. These findings will advance our understanding of tumor progression and metastasis and may credential TKI258 as a new therapy for advanced prostate cancer.
William Oh, MD – Mount Sinai School of Medicine, New York
Predicting Response to Platinum Chemotherapy in Metastatic Castration-Resistant Prostate Cancer (CRPC) Using a Genomic Signature for “BRCAness”
Every cell has DNA repair mechanisms that function to protect DNA from harmful mutations which can cause cancer and cell death. In healthy cells DNA repair mechanisms are intact but in cancer cells they are often but not always damaged. Platinums are a class of chemotherapy medicines that kill cancer cells by damaging the cell’s DNA structure. However, certain types of cancer cells are more susceptible to DNA-damaging drugs like platinum than others. Satraplatin is a type of platinum that is unique; it can cause more severe DNA damage than its counterparts. Yet, BRCA1 and BRCA2 are two genes that may predict satraplatin activity and confer therapy sensitivity. Importantly some patients carry BRCA1 and BRCA2 mutations resulting in limited DNA repair function. Dr. Oh hypothesizes that patients with loss of BRCA1/2 function will benefit more from satraplatin therapy–particularly if the cancer is anaplastic–because the cancer cells lack the ability to repair themselves. This award will fund a prospective Phase II clinical trial of satraplatin in metastatic prostate cancer patients that will determine whether patients with mutated BRCA1 and BRCA2 genes are more sensitive to satraplatin therapy. Such findings will advance personalized medicine in prostate cancer treatment strategies and can be applied to newer drugs that also target this DNA repair pathway.
Renata Pasqualini, PhD – The University of Texas MD Anderson Cancer Center
Implications of Obesity in Prostate Cancer Recurrence and Progression- A Novel Fat-ablating Strategy to Overcome the Cancer Promoting Effects of Obesity
Obese men are more likely to develop aggressive prostate cancer and to experience disease recurrence than normal weight men. The significant level of adipose tissue (fat) in obese men has therefore been implicated as a critical contributing factor in poor prostate cancer outcome. Adipose tissue can be categorized into two different types: white fat and brown fat. White fat has been identified as the “bad” fat for cancer, and is most abundant in obese men. Prohibitin-TP01 is a new agent, discovered in Dr. Pasqualini’s lab, which specifically targets the vasculature that nourishes white fat. Preclinical studies in mouse models showed that TP01 treatment reduced white fat and resulted in ~30% weight reduction. Dr. Pasqualini’s goal is to successfully translate Prohibitin-TP01 into the clinic as a new agent for obese men with advanced prostate cancer.
Kenneth Pienta, MD – University of Michigan
Analysis of Primary and Metastatic Prostate Cancer from Men with Untreated Prostate Cancer
The goal of this project is to develop a comprehensive biorepository from individuals with untreated primary and metastatic prostate cancer to 1.) better define the molecular basis for prostate cancer progression, 2.) discover new biomarkers of aggressive and potentially lethal prostate cancer, and 3.) identify new therapeutic targets for this disease. Dr. Pienta and colleagues have proposed to collect serum, circulating tumor cells (cancer cells that broke away from the tumor and entered circulation), DNA, plasma, urine and biopsies from the primary tumor and metastatic sites including bone, lymph nodes and other soft tissue sites of cancer involvement. This biospecimen repository will be unique because these patients’ metastatic site samples are pre-treatment. Autopsy specimens of metastatic prostate cancer that had been treated are useful. However, the selective pressure of long-term treatment exposure causes distinct molecular changes and cellular selection of a patient’s tumor cells which complicates molecular studies of tumor progression and hinders the identification of therapeutic targets. All of these biospecimens will be analyzed using high-throughput molecular biotechnologies and will be made available to the global research community.
Matthew Rettig, MD – University of California, Los Angeles
A Nano-Structured Platform for Enhanced Detection of CTCs in Prostate Cancer Patients
Circulating tumor cells (CTCs) are cancer cells that break away from either the primary tumor or metastatic lesions and enter blood in circulation. There is great interest in CTCs because they have the potential to provide clinicians with vital information of a patients’ cancer and are accessible (“liquid biopsy”) without having to perform an invasive tumor tissue biopsy. CTCs can be captured using a variety of technologies. A technical challenge has been to capture a sufficient number of viable CTCs to conduct molecular studies. Dr. Rettig and his team at UCLA have developed a novel and inexpensive cell capture system applying complex nanotechnology and cell biology to collect large numbers of viable CTCs from patients with metastatic prostate cancer. The collection of viable CTCs will enable Dr. Rettig’s group to define the molecular alterations in prostate cancer cells that confer progression and lethality. Ex vivo (outside of the body) preparations of patient CTCs will also be useful in selecting appropriate therapies for individual patients and for refining their prognosis. Success of this project will translate into more informed treatment strategies and may identify new therapeutic targets.
Matthew Smith, MD, PhD – Massachusetts General Hospital
Prospective Translational Study of Metformin in Castration-Resistant Prostate Cancer
Recent population-based studies have shown that type 2 diabetic men treated with Metformin, a medicine that lowers insulin levels in blood, have lower prostate cancer incidence and improved prostate cancer specific outcomes. These findings provoked the hypothesis that higher insulin levels promote prostate cancer growth. Dr. Smith and colleagues propose to investigate the efficacy of Metformin in a prospective clinical trial for patients with progressive prostate cancer who have failed hormonal therapy. During this clinical study the investigators will monitor changes in the metabolic profile (a catalogue of hormones and chemical byproducts indicative of cellular processes) of patients’ blood and correlate results with clinical response. This study will provide essential information on the anti-tumor effects of Metformin and may credential Metformin as a new agent for prostate cancer therapy.
Scott Williams, MD – Peter MacCallum Cancer Centre, Australia
Exploration of the Relationship between In Vivo Molecular Imaging, Cellular Response and Therapeutic Outcome in Irradiated Human Prostate Cancer
A common treatment for localized prostate cancer is radiation therapy. Currently, the two most widely used types of radiation therapy are external beam radiation and brachytherapy (implantation of radioactive seeds into the prostate gland). Yet given the frequency of radiation therapy procedures, few studies have explored how patient tumors respond to radiation and why certain tumor cells are resistant. Dr. Williams’ will perform a clinical investigation that uses molecular imaging and molecular analysis of biopsies before and after radiation therapy to identify predictive markers of response and resistance to radiation therapy. This study will advance the optimization of radiation therapy for prostate cancer patients.