Progress Report

1) Programmatic Initiatives. Over the past year, the SPORE has instituted or changed a number of internal activities to strengthen the education and collaborative aspects of the program. A notable initiative has been the institution of a new quarterly SPORE investigator progress meeting. Each quarter, all SPORE investigators (major projects and career development/developmental research ones on a rotating basis) meet for 2 hours to present brief progress reports to the group. This meeting serves (1) to create a sense of cohesion within the program (2) to stimulate dialogue and feedback between investigators, particularly clinical and basic members, and (3) to enhance close working relationships between the projects and the cores. An indirect benefit of this meeting has been to enhance the information flow to the Executive and Internal Advisory Committees, enabling them to better assess progress and make recommendations to the investigators. To date, we have had two quarterly investigator meetings, both of which have been universally considered a major improvement in the conduct of the program. The third quarterly investigator meeting is scheduled for June. A second minor change has been to enhance the bimonthly seminar series by moving it from late afternoon to noon in order to increase participation among both SPORE and non-SPORE investigators and by increasing the number of internal presentations by developmental awardees. Attendance has increased dramatically, which will enhance the visibility of the program and serve to recruit new investigators into the field.  Seminars are alternated between extramural speakers and intramural ones (a major project and/or career development/new project awardee speak at each intramural seminar).

2) Major projects:

1. Imaging PSCA in Prostate Cancer: This project has made tremendous progress in a short period of time. Most notable is the critical selection of a lead engineered fragment to take into the clinic and the generation of a high-expressing clone. There has also been progress in the generation of the human PSCA knock-in model system, with the identification of positive ES clones that should lead to the development of a human PSCA knock-in model over the next year. Budgetary and technical discussions with the City of Hope GMP facility have been completed and the PSCA minibody is first-in-line for production over the coming 18 months. UCLA urology funds will be used to leverage SPORE moneys to complete GMP production. During this time, regulatory materials will be compiled so that an exploratory clinical trial can begin in a timely manner.

2. PI3K Pathway Inhibition in Prostate Cancer: Significant progress has been made in all Aims, particularly the preclinical studies of Aims 1 and 2 that identify molecular signatures of PI3K-driven tumors and that assess combination therapies targeting upstream and downstream members of the pathway. These should lead to the rational selection of agents for neoadjuvant and other studies proposed in Aim 3. Also, additional analysis of the complete neoadjuvant mTOR trial has been completed, with a publication of results anticipated over the coming year.

3. Lympangiogenesis and Metastasis in Prostate Cancer: Dr. Lily Wu’s group has made significant progress on all Aims. Specifically, her group has established all histologic staining conditions to assess all members of the lymphangiogenic axis in human tumors in collaboration with the Pathology core. Proof-of-principle preclinical studies demonstrating the efficacy of VEGF-C and VEGFR-3 blockade have been completed and submitted for publication. These studies showed a reduction in tumor lymphangiogenesis and metastasis to regional lymph nodes. Interestingly, their studies showed that VEGF blockade had no effect on lymphangiogenesis, suggesting that antiangiogenic therapy might fail because of its inability to block lymphatic tumor spread. Finally, her group has published a report in Nature Medicine showing the promise of prostate specific imaging to detect lymphatic metastasis. These studies are highly translational and will complement the recently initiated trial of the VEGFR3 inhibitor Sorafenib begun at the University of Washington SPORE.

4. Development of IGFBP3 Therapy: Major progress has been made in the translation of recombinant IGFBP3 into the clinic. A clinical trial protocol has been submitted to the IRB, as well as to the Data and Safety Monitoring Board of the Cancer Center. GMP products are being manufactured by Insmed and IND submission is in the process of being completed. This progress gives confidence that we will be able to complete translation of this UCLA-discovered drug into the clinic during this SPORE cycle. Dr. Cohen’s group has also demonstrated over the past year the requirement of IGFBP3 for prostate cancer apoptosis and its mechanism, providing additional rationale for translation.

5. Dietary Fat Modulation in Prostate Cancer: This project has also made tremendous progress during the current cycle, meeting target enrollment that was promised during the competitive renewal. Specifically, 21 subjects have been enrolled since September 2007, bringing total enrollment to 51/70 subjects. Completion of enrollment is anticipated by 18 months into the renewal cycle, as promised. Preliminary results have also been obtained for the first 13 subjects, showing the ability of dietary changes to alter membrane fat composition changes, as well as a reduction in COX-2 staining. These very promising initial results will be studied at the molecular level in order to determine the specific pathways that are critical for cancer growth, which can be altered with diet. Finally, we anticipate the ability to begin a follow-on study combining dietary and molecular interventions to augment these changes.

3) Developmental grants: A major facet of the UCLA SPORE is the development of new investigators and novel projects that can augment the translational research effort at UCLA and elsewhere. We are particularly interested in bringing senior investigators without a previous interest in prostate cancer into the field, especially those from outside the traditional molecular biology and clinical realms. This focus has paid tremendous dividends in the past. Examples include Anna Wu, an applied imaging expert, who was recruited to develop new imaging tracers for prostate cancer, and Samedy Ouk, a chemist who collaborated with Charles Sawyers to develop small molecules targeting the androgen receptor. MDV3100, a small molecular AR antagonist, resulted from this entirely SPORE-supported work. This molecule has now completed Phase I trials and shown dramatic anti-tumor activity in hormone refractory patients.

The recent cycle was announced in October and awards were announced in late December 2007. Career development investigators include (1) Samson Chow, a senior investigator who has not preciously worked in the prostate cancer field, who will study the role of the XMRV virus in prostate cancer, (2) Eric Lepin, a senior postdoctoral student, who will develop F18 labeled diabodies to image prostate cancer by PET and (3) Arnold Chin, an MD-PhD urologist, who will continue his work on Toll receptors in prostate cancer. Among the developmental projects awarded were (1) Stephen Smale, another senior investigator entering the prostate cancer field, who will take a high-risk, high-reward approach to developing small molecule modulators of immune response (2) Matt Rettig, a medical oncologist, who will attempt to identify new androgen receptor transcriptional inhibitors, and (3) Nori Kasahara, a gene-therapy expert, who will develop a new generation of prostate-targeted approaches to gene therapy. We also continue to support previous awardees who made progress in their first year of support.