New Faculty II
$3 203 965
Prostate cancer is the most common non-skin cancer in American men, and disease which has spread out of the pelvis is incurable and constitutes the second highest cause of cancer mortality in this group. Recently it was shown that not all prostate cancer cells are the same: A small number of unique cells within the prostate tumor are able to self-renew and to produce more tumors much more rapidly and efficiently than the rest of the cancer cells. Because of this ability, these cells have been named prostate cancer stem cells (PCSCs). It has been suggested that current available treatments, like hormone therapy or chemotherapy, may only be killing the rest of the prostate cancer cells but are leaving behind the PCSCs, which grow into new tumors that eventually spread and claim the lives of patients. Therefore, a new treatment strategy may be necessary to efficiently target and eliminating these unique prostate cancer stem cells. My lab is well-positioned to investigate a new, PCSC-specific treatment approach: We are experienced in isolating cancer cells from patient tumor tissue, and we possess special expertise in the study and modulation of telomerase, an enzyme that protects the ends of chromosomes, the structures which contain a cell’s DNA. Telomerase protection of chromosome ends allows cells to continue dividing; therefore, telomerase plays a critical role in cells that continue to divide and grow, such as stem cells and cancer cells. In addition to laboratory expertise, my direct care of prostate cancer patients provides access to tumor tissues for study and to clinical data that can be correlated to our laboratory findings. This combination of laboratory and clinical resources offers a unique opportunity to isolate and study PCSCs. Given this background, we propose to study whether advanced prostate cancer is associated with increasing numbers of PCSCs and increased PCSC telomerase activity, and whether interfering with PCSC telomerase function can reduce the ability of these cells to form new tumors. To investigate this question, we will 1. Measure PCSC numbers and PCSC telomerase enzyme in early versus advanced prostate tumors isolated from patients and from mice; the patient data also will be correlated to clinical prognosis; 2. Interfere with PCSC telomerase function and measure the impact on cancer cell functions previously shown to be affected by telomerase, such as gene expression, DNA damage, and cell death; and 3. Interfere with PCSC telomerase function and measure the impact on the PCSCs’ ability to form new prostate cancer tumors. Through this innovative yet comprehensive approach, we will demonstrate the role of PCSCs and PCSC telomerase in advanced prostate cancer, and we will test a promising new therapeutic strategy for this devastating disease.
Statement of Benefit to California:
California’s population, like that of the United States as a whole, is becoming older. Increasing median lifespan, together with the aging “Baby Boomer” generation, will combine to effectively double the over-65 age group in the next 20 years (U.S. Census Bureau Data). Prostate cancer, perhaps more than any other disease, is associated with advancing age and constitutes the second highest cause of cancer death in American men. The cumulative lifetime risk of prostate cancer is 1 in 6, the highest of any cancer, and the majority of that risk is incurred late in life: the probability of developing prostate cancer roughly doubles from the 7th to the 8th decade of life (ACS Cancer Statistics). The sheer volume of expected new prostate cancer cases in our aging population necessitates aggressive new treatment strategies with the potential to significantly reduce the immense individual and societal tolls projected for this devastating disease. One such approach involves studying and targeting a recently-discovered subset of prostate tumor cells that have been dubbed “prostate cancer stem cells” (PCSCs). These unique cancer cells resemble normal stem cells and have the capacity to self-renew and to generate new tumors, just as normal stem cells can renew and generate new tissue. It has been suggested that PCSCs may evade the hormone treatments and chemotherapies currently available for prostate cancer, eventually leading to incurable metastatic disease. In our research project, we propose to measure the numbers of PCSCs in early versus advanced prostate cancer tumors from patients and from mice, and also to measure the activity of telomerase within PCSCs. Telomerase is an enzyme that is intimately linked both to cancer progression and to stem cell activation and may therefore be an effective target for controlling PCSCs. In our planned experiments, we will determine whether PCSC numbers and PCSC telomerase activity do in fact correlate with advancing prostate cancer and poor prognosis, and we will test whether interfering with telomerase can prevent PCSCs from producing more tumors. By studying PCSCs and telomerase, we hope to provide new avenues for treating hormone and chemotherapy resistant prostate cancer, thus helping to control and perhaps ultimately to eliminate this disease from our aging population.
Prostate cancer occurs in 1 of 6 men and accounts for nearly 30,000 deaths annually in North America. Recently a population of cells that self-renew and have high tumorigenicity was isolated from primary prostate tumors and cell lines. It has been proposed that these prostate cancer stem cells (PCSC) may be responsible for resistance to current therapies and for tumor progression and metastases. Thus, targeting these cells may hold the key to achieving durable cancer cures. Proliferating human tumor cells express high levels of telomerase. The applicant discovered that interfering with expression of telomerase induces a DNA damage response in tumor cells resulting in apoptosis. The applicant hypothesizes that telomerase activity can be used as a biomarker of PCSCs and that targeting this enzyme will cause the death of these cells. S/he proposes to determine whether there is a correlation between clinical correlates of disease progression in human and mouse prostate tumors and telomerase activity in prospectively purified PCSCs. The applicant will investigate whether interference with PCSC telomerase function causes DNA damage, alters gene expression, and induces apoptosis of tumorigenic/clonogenic PCSCs and finally, whether interfering with PCSC telomerase function reduces the tumorigenic potential of this cell population. The applicant believes that she/he is in a unique place to investigate novel, PCSC-specific therapeutic approaches because she/he is an expert in telomerase and has direct care of prostate cancer patients and access to excellent disease models that provide unique opportunities to isolate and study PCSCs. Despite this, the reviewers all commented that although a compelling case was made for the proposed studies, there are many flaws in the described experimental plan, as well as technical challenges that were not addressed in the research proposal. Specifically, the abundance of PCSCs is very low even in purified populations of these cells, and the tumors are small, limiting the number of cells that can be isolated. Furthermore, telomerase activity is not uniquely expressed in PCSCs but is also found in all dividing tumor cells, which will comprise many of the cells even in the “purified” PCSC populations. These factors will confound any attempt to correlate clinical markers of cancer progression with telomerase activity in PCSCs. The reviewers also commented on the importance of determining whether interfering with PCSC telomerase function will reduce the tumorigenic potential of this cell population as assessed by transplant experiments prior to understanding mechanisms. The reviewers were also unclear on and lacked confidence in the applicant’s familiarity with the means of assaying functional and clonogenic PCSCs based on the limited information provided. The applicant is a young physician-scientist who the reviewers considered to be very well qualified in clinical medicine but lacking in adequate research experience. This assessment reflects the applicant’s publication record that includes only a single publication resulting from three years of post-doctoral studies and little evidence for training in stem cell biology. The applicant has been awarded an NIH KO8 award, given to promising young investigators. The reviewers commented that the applicant had a good career development plan that emphasized his/her commitment to academic medical research and need for the current support to meet those goals within the next five years. The institution’s support for the applicant is strong based on amount of protected time provided for research, the more than adequate resources, and mentoring from excellent investigators. The institution has agreed to provide 75% protected time for research of which 50% is proposed to be devoted to the research proposed in this application. The applicant’s mentors are eminent researchers in cancer and stem cell biology and provide strong supportive letters. A reviewer commented that the institution’s stem cell program and cancer center are well known. Overall the reviewers had more enthusiasm for the applicant and the institutional support and environment provided to the applicant than for the research proposal. They considered the general idea promising but the plan for implementation flawed.