PCF’s 18th Annual Scientific Retreat: A Report
For information on the 2012 PCF Scientific Retreat, please see here
An update from Dr. Jonathan W. Simons, President and CEO of the Prostate Cancer Foundation:
PCF’s 18th Annual Scientific Retreat was the best meeting ever organized by PCF as measured by multiple data points—number and breadth of attendees, the quality and topics of the presentations and attendee and Board member feedback. It was also the largest. We ran out of rooms and turned away many.
Nearly 350 attendees representing 83 academic institutions, 30 biopharmaceutical companies and 7 medical research foundations from 11 countries gathered to share the latest advances in research to find better treatments and cures for patients. We were also honored to have 11 of our Board members and 24 major donors join us for the meeting. Andy Von Eschenbach, former Director of the NCI and FDA Commissioner, and a long-time friend of PCF, was also present.
Not surprisingly, the 47 PCF Young Investigators who participated in the meeting continue to prove themselves as a formidable force in forwarding innovative ideas and accelerating discovery. During our pre-Retreat meeting with our YIs, we were impressed to receive unpublished data on 8 new targeted drug ideas for patients with advanced disease. Eleven YIs provided featured presentations accounting for nearly 25% of the meeting content. In all, 45 presentations, representing 17 topic areas were shared with attendees.
Saturday morning, we were honored to have a special added session moderated by Mike Milken. The discussion focused on closing the gaps between research institutions, the pharmaceutical industry and the FDA to improve sharing of data, define new clinical study endpoints and speed approvals of new medicines for patients. Joining the panel were Francis Collins, Director of the NIH, Margaret Hamburg, Commissioner of the FDA, Leroy Hood, co-founder and President of the Institute of Systems Biology, Chris Viehbacher, CEO of Sanofi-Aventis and President of PhRMA, and Elias Zerhouni, former Director of the NIH and advisor to the CEO of the global pharmaceutical and vaccines company, Sanofi-Aventis, on science and technology issues. Zerhouni is also a Professor of Radiology and Biomedical Engineering at Johns Hopkins University. The discussion was a passionate one on the need for transparency, more resources, coordination and consistency of approaches between government, industry, and academic partnerships. The session provided the first opportunity for many of our attendees to interact with these impressive panelists.
As always, a full synopsis of all the meeting’s new data and key points will soon be published and available for review on pcf.org. Meanwhile, I would like to provide you with brief overviews of several exciting research developments that were discussed at the Retreat.
New Understanding and Treatments for Bone Metastases in Advanced Disease
Each year, approximately 300,000 American patients suffer from bone metastases. These metastases contribute to significant morbidity and mortality in patients with advanced cancer. PCF saw continued progress in better understanding the mechanisms of prostate cancer bone metastases and treating this painful and life-threatening manifestation of advanced disease.
Deciphering how bone metastases form—Russell Taichman, DMD, a dentist-scientist from the University of Michigan has been working with PCF-funded researcher, Ken Pienta, MD. His research provides insight into the mechanisms used by cancer cells to settle in the bone during cancer progression and metastasis. Dr. Taichman has discovered that circulating prostate cancer cells can invade the hematopoietic stem cell niche, an area of the bone where blood stem cells reside and produce the components of blood. Once prostate cancer cells displace the rightful residents and settle into this area, they can lay dormant until they begin multiplying and form a tumor in the bone. Taichman's team discovered the reason prostate cancer cells occupy the blood stem cell niche in bone is that, surprisingly, metastatic prostate cancer cells are programmed to grow well in the exact same environment where blood cells form. As Taichman said it colloquially, prostate cancer cells "go home" to the bone.
Metastic prostate cancer cells compete for the Hematopoietic Stem Cell niche in the bone, pushing out HSCs (blood stem cells) and establishing cancerous lesions in the bone.
Dr. Taichman has studied agents that coax invading prostate cancer cells from these bone niches and force them back into the blood stream where therapeutic agents can destroy them. These findings hold promising potential for the treatment of metastatic prostate cancer lesions by "kicking prostate cancer cells out of the hematopoeitic stem cell nest" and letting the healthy normal blood stem cells have the nest back.
Alpharadin (radium-223 chloride) a promising new therapeutic—Oliver Sartor, MD, from Tulane University, provided Retreat attendees with an in-depth overview of the development of an exciting new therapeutic, Alpharadin (radium-223 chloride) which is about to be approved in Europe and the US. It is an investigational alpha-pharmaceutical (containing an alpha-particle-emitting nuclide) in development for cancer patients with bone metastases. This compound is "first in class" and is atomically like calcium. It mimics many of the behaviors of calcium including quick uptake into the bone, particularly where calcium is being deposited, in bone metastases.
In the Phase III clinical trials, Alpharadin improved overall survival by about 3 months for patients with castration-resistant prostate cancer and bone metastases without affecting patient's bone marrow functions and forcing transfusions of platelets or red blood cells. Based on a recommendation by the Independent Data Monitoring Committee (IDMC), the clinical trial was stopped and patients on the placebo were given the option to receive the drug.
Alpharadin treatment is the first of its kind. By decaying radioactively in the bone metastatic site, Radium 223 fires off an alpha particle of energy that kills nearby prostate cancer cells. Alpharadin enters a patient’s bone and disperses small amounts of “short-range, high-energy” radiation, attacking the prostate cancer and preserving healthy cells surrounding the tumor. The Prostate Cancer Foundation was the first foundation to fund the proof of concept of radiopharmaceuticals at University of Texas MD Anderson Cancer Center through Dr. Christopher J. Logothetis using beta particles. When approved by regulatory agencies, Alpharadin will be the 5th new agent in a growing number of new drugs that have been approved for increasing survival of men with mCRPCA in the past 18 months. Alpharadin is intriguing as it could be combined with new immunotherapy approaches.
Studying XL184 (Cabozatinib) anticancer activity and its ability to shrink tumors in bone and soft tissue—PCF-funded investigators, Matthew Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center and Phillip Febbo, MD, at UCSF, held a discussion on XL184.
Abnormal MET activation (a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor--HGFR) in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis). Vascular endothelial growth factor (VEGFR2) is a central regulator of the angiogenic process in tumor angiogenesis and the proliferation of tumor cells. In early clinical trials, Cabozantinib (XL184), a dual inhibitor of MET and VEGFR2, has shown promising results in shrinking metastatic tumors in both bone and soft tissue in patients with advanced prostate cancer.
While most cancer therapies to date have modest effects on bone metastases, tumor shrinkage is observed in a majority of patients who are given Cabozantinib: at week 12, there was a 74% control rate of tumors in prostate cancer patients: complete or partial bone scan resolution in 85% of PCa patients; and stabilization was achieved in 13% of PCa patients. These positive results were accompanied by pain relief and impressive bone scan improvement and were observed in castrate-resistant prostate cancer as well as breast cancer, melanoma, renal cell carcinoma, and thyroid cancer.
While studies of the most effective dosing continue, patient tolerance of Cabozantinib is consistent with other tyrosine kinase inhibitors and its manufacturer, Exelixis is planning to initiate its first pivotal trial in castrate-resistant prostate cancer by the end of this year. Dr. Febbo provided his perspective on the mechanism of action of XL184. He suggested that both receptor tyrosine kinases, c-Met and VEGF-R2, are critical in bone metastases and, when their signaling is blocked together—with a single drug that acts on both—a therapeutic effect is achieved. Neither c-MET nor VEGF-R2 were implicated as central in treating bone metastatic disease 24 months ago in prostate cancer research and both now are the focus of intensive research funded by PCF.
Xgeva update—In related news, the use of Xgeva (denosumab) to prevent bone deterioration and fracture in patients undergoing hormone therapy (ADT) was approved by the FDA just days prior to the start of the Scientific Retreat. Approval of a second indication of Xgeva—to actually delay or prevent metastases to the bone—is currently under review. The FDA has indicated that it will make an approval decision by April 2012. Dr. Smith, who has long focused on improving survivorship in men with advanced disease, has led Xgeva studies over the past few years.
New Insights to Targeted Chemotherapy
Taxanes (taxol, taxotere, cabazataxel) are 20th century chemotherapeutic drugs and currently the first line of therapy for patients with metastatic prostate cancer. They were FDA-approved before their exact mechanisms of action were known, and now the drug class is progressively being deciphered for better medication design.
The opening session of PCF’s Retreat reported the latest findings on taxanes in killing prostate cancer cells. Taxane drug molecules bind microtubules and prevent their decomposition. As the building blocks for the formation of newer tubules becomes unavailable, the growth of the cancer cell is arrested, eventually leading to cell death (apoptosis).
Dr. Michael Morris, of Memorial Sloan-Kettering Cancer Center, focuses on understanding why chemotherapy works for some patients and not others, as well as understanding what combinative treatments might work best for certain patients. He provided an historic perspective on the use of taxanes in the treatment of advanced prostate cancer.
Morris summarized his presentation by raising three very important questions that should be addressed in the field; one, WHO are the patients that are most suited for chemotherapeutic treatment; two, WHEN in the treatment regimen should chemotherapy be delivered and three, WHAT are the best chemotherapeutic combinations for the most effective therapy that avoid past pitfalls in treatment.
Natasha Kyprianou, PhD, of the University of Kentucky, presented research data providing insight into the reasons for the failure of paclitaxel as a chemotherapeutic for metastatic castration-resistant prostate cancer (mCRPC). The results demonstrate a new mechanism of action for docetaxel, linking AR signaling and taxane chemotherapy in prostate cancer.
Resistance to hormone therapy develops as cancer cells start overexpressing the androgen receptor (AR) which translocates from the cellular cytoplasm to the nucleus to activate genes that promote cancer growth and invasion. Taxanes have been shown to be effective first line chemotherapeutics for the treatment of CRPC, however their mechanism of action still remains unclear. Dr. Kyprianou’s team studied the effect of taxane chemotherapy on androgens and the AR signaling axis.
The research team’s findings show that AR is transported to the nucleus via microtubules, with AR interacting directly with the microtubule-building block, tubulin. Therefore, taxanes that affect microtubule organization interfere with AR nuclear localization and activity in human prostate tumors. As AR is unable to reach the nucleus, it is unable to activate genes for cancer growth (e.g., PSA) and this is reflected in the decrease of PSA gene expression in human prostate tumors.
Dr. Kyprianou also demonstrated that tubulin interacts with AR specifically at the latter’s N-terminal domain, which serves as an ‘engine’ for AR activity. Therefore, chemical inhibitors such as EPI-001 that specifically target the AR N-terminus can inhibit the AR-tubulin interaction, further preventing AR transport to the nucleus. This was reflected in the reduction of tumor volume when mice were treated with a combination of taxanes and EPI-001. Thus these exciting new findings attribute a new mechanism of action to taxanes as well as provide initial evidence for the use of taxanes in combination with EPI-001 for the treatment of metastatic treatment-resistant prostate cancer.
Evi Giannakakou, PhD, of Weill Cornell Medical College, presented data on using circulating tumor cells to dissect mechanisms of clinical taxane resistance to study and predict prostate cancer patients’ clinical response and resistance to taxane chemotherapy. Dr. Giannakakou’s team further confirmed the results observed by Dr. Kyprianou, that the androgen receptor (AR) uses cellular microtubules for its translocation into the nucleus. These findings also re-iterate that taxanes inhibit AR-induced activation of cancer-specific genes, because these microtubule-stabilizing chemotherapeutics cause the sequestration of AR in the cytoplasm.
However, in contrast to the results from the University of Kentucky, these findings demonstrate that the C-terminal domain (as opposed to the N-terminus) of AR is essential for its interaction with the microtubules. The finding with the most translational significance from this work was the fact that taxanes inhibit AR nuclear translocation in CTCs isolated from CRPC patients’ blood. This taxane-induced blockade to nuclear accumulation of the AR predicts clinical responses to taxane chemotherapy in metastatic prostate cancer.
Patients express several variants of AR and Dr. Giannakakou showed that the variant ARv7 does not depend on microtubules for its translocation into the nucleus. Therefore, patients with this AR variant will not benefit from taxane chemotherapy; while on the other hand, patients with the Arv567 variant are highly sensitive to taxane therapy. It is going to be important to develop "actionable" tests for patients based on androgen receptor variants that could predict, in advance, sensitivity or resistance to taxane based chemotherapy.
In collaboration with Drs. David Nanus, Cornell University, and Steven Plymate, University of Washington, Dr. Giannakakou has developed a system that can identify AR variants and their cellular localization in patients that employs a PSMA-based microfluidic Geometrically Enhanced Differential Immunocapture (GEDI) device. This information can then inform potential response to taxane chemotherapy. Thus the ability to isolate and study single CTCs from patients can predict clinical response/resistance to taxanes.
Martin Gleave, MD, presented on the role of Clusterin, a molecule that contributes to prostate cancer cell survival which can be inhibited by a new target agent, OGX-011. This new therapeutic is currently in late-stage clinical testing in combination with docetaxel chemotherapy.
Finally, Ahmed Ashour Ahmed, MD, PhD, from the University of Oxford, a researcher currently studying the response of ovarian cancer patients to a taxane named paclitaxel, presented his findings. He proposes that pharmacologic modification of microtubule stability can increase patient response. His team has identified a protein called TGFBI (Transforming Growth Factor Beta Induced) that sensitizes cancer cells to taxane treatment. PCF prides itself in bringing new people with unique expertise to our field. Dr. Ahmed is an example of a physician-scientist working on ovarian cancer therapy who might better inform treatment strategies for prostate cancer. Enhanced Imaging Techniques for "Seeing" Unseen Prostate Cancer Molecular imaging to detect early recurrent metastatic prostate cancer is a significant unmet medical need. Dr. Steven Cho (The Peter and Laurie Grauer-PCF Young Investigator) and colleagues at Johns Hopkins University presented results on the early clinical testing of a molecular imaging technology that appears very promising.
Prostate-specific Membrane Antigen (PSMA) is a prostate cancer-specific cell surface marker. The expression of PSMA increases 8-12x during prostate cancer progression and metastasis and increased expression is linked with more aggressive disease and recurrence. PSMA that is “lit up” chemically is being targeted as an imaging biomarker for the detection of early metastatic prostate cancer by Dr. Cho and his research team. Small molecule binders to PSMA have been coupled to PET imaging tracers. When injected into patients, the PSMA-directed PET tracer will permeate and bind to prostate tumors and can be detected by PET scanning the patient with equipment readily available in most hospital settings.
Dr. Cho presented his results from a Phase I, first-in-human study of one such PSMA PET tracer (Flourine-18-labeled DCFBC). DCFBC is an excellent radiotracer as it is stable for only two hours, making it practical for clinical translation.
In this study, Dr. Cho studied the safety, biodistribution (where the tracer binds and is eliminated) and radiation dosimetry (the quantity of tracer present in all organs and blood) in five metastatic prostate cancer patients. These subjects had PSA>1 and radiologic evidence of new or progressive metastatic disease. None of the patients experienced any adverse side effects attributable to the radiopharmaceutical, which could conclusively detect both primary as well as metastatic prostate cancer lesions. The early PET scans demonstrated the localization of prostate cancer not detectable by routine bone and CT scans.
Dr. Cho’s early results show that PSMA-targeted PET scans can detect locally advanced or progressive prostate cancer before existing, routine imaging technology. Early detection will result in earlier treatment with the potential to prevent widely metastatic prostate cancer.
Improving Outcomes in Advanced Prostate Cancer with Experimental Agents
Also at the Retreat, Dr. Johann de Bono MD, PhD, at the Institute of Cancer Research and The Royal Marsden Hospital in London, emphasized that “biomarker-driven, well-designed and expertly-conducted reiterative and adaptive clinical trials will change cancer medicine through the questioning and answering of robust scientific hypotheses utilizing rationally designed and molecularly targeted drugs.” He re-iterated the need to update the Pharmacological Audit Trail (PhAT), from the previous paradigm of directly testing drugs in all patients to see who respond best, to a rationally designed approach of first determining the molecular profile of a patient’s tumor and then administering the most appropriate medication.
With a focus on molecular-targeted therapies, Dr. de Bono is a proponent of testing all hypotheses using biomarkers in clinical trials. This biomarker-driven trial design enables molecular stratification of patients based on their response. This "enrichment" of the study—followed by scientific patient selection with actionable biomarkers—is accelerating the testing and development of new classes of anti-cancer drugs. The biotechnology and pharmaceutical industry is also getting "indoctrinated" with the success of the current wave of targeted drugs that are evaluated in this way.
Dr. de Bono has been instrumental in developing new molecular targeted therapies to improve treatment for prostate cancer patients. Using the National Health Service in the United Kingdom as a referral system, de Bono's team outside of London is currently evaluating more than 20 drugs in early clinical trials and has recently led the Phase III trials for abiraterone and cabazitaxel, both of which showed an overall survival benefit in patients with advanced metastatic, castration-resistant prostate cancer.
We had in the audience at least 20 prostate cancer survivors including Dan Zenka, our senior vice president of communications, who is also a patient with advanced disease. During Prostate Cancer Awareness Month, we heard Dan tell an audience, who had come to celebrate the inaugural blue lighting of Los Angeles’ City Hall for National Prostate Cancer Awareness Month: “If you must be given a diagnosis of prostate cancer, there is no better time than today to be a patient…” As I look back on the results of PCF-funded science that was shared at this Retreat, I believe his observation is really accurate.
Our research community is zeroing in on more “druggable” mechanisms and pathways of advanced prostate cancer (e.g., PARPness, ERGness,
HSP27ness, c-METness, SPINKness) and the global PCF funded research community is moving more "first in field" drugs to patients in the US, Canada, the UK and Europe. This Retreat really was the science unfolding to put patients back into remission in real time.
Positive responses via email to this year’s Retreat continue to come in at this writing. We posted them on the front of the PCF staff refrigerator next to the coffee pot, but we ran out of refrigerator surface area. Dr. Howard Soule and his staff and the PCF Program Committee raised an incredibly high bar for 2012's Scientific Retreat.
Here are two of the representative comments:
“I have to be honest. I was really upset to have to leave a day early. I don't know quite why I missed out the last two years… This is THE prostate cancer meeting! I had to tear myself away."
–Johann de Bono, MD, PhD, Royal Marsden Hospital and The Institute of Cancer Research, London
“I can only say that the past few days have been nothing short of enlightening. I have been, since this morning, and will be spending much time in the next weeks thinking through all the progressive ideas and science that was packed into what turned out to be too short a time in gorgeous Tahoe.”
–James McCullough, CEO, Exosome Diagnostics
Our sincerest appreciation goes to our Board members, donors, PCF’s research family, industry partners and staff for making this 18th Annual Scientific Retreat possible.
Again, in-depth discussion of these topics and more will soon be published on this site for your review.