Targeted Therapy in Prostate Cancer: Is There Hope Beyond the Androgen Receptor?

Derleth and Yu provide a comprehensive overview of the current landscape of agents that target androgen receptor (AR) signaling and other molecular targets in prostate cancer, with an emphasis on phase III clinical trials. We would like to begin by complementing the report with some additional context-an historical accounting of targeted therapies that have left the battlefield humbled and defeated. Even when one limits that historical perspective to targeted therapy trials that included docetaxel (Taxotere), the record of phase III trials is 0 for 8. The Table provides a summary of this disappointing history.

TABLE

Main Results From All Reported Phase III Trials of Targeted Therapies in Combination With Docetaxel (Taxotere) in Metastatic Castration-Resistant Prostate Cancer

In recent years, phase III trials of several classes of broadly acting agents, including chemotherapy, immunologic therapy, and a radiopharmaceutical, have demonstrated improved survival.[9-12] However, it is striking that the contribution of targeted therapies to this progress has been limited to a single target-the AR. Indeed, AR has been the principal therapeutic target in prostate cancer for over 70 years.[13]

AR and androgen ligands that activate the AR have proven important time and time again for promoting castration-resistant prostate cancer (CRPC) progression through a variety of mechanisms. These include: AR gene amplification, AR splice variants, AR mutations, and alterations in AR binding proteins.[14-20] AR is a particularly compelling target because resistance to androgen deprivation therapies (ADTs) frequently occurs in the setting of persistent synthesis of intratumoral androgens.[21-23] The effectiveness of newer and more potent forms of ADT-abiraterone (Zytiga)[24,25] and enzalutamide (Xtandi)[26]-that improve survival in phase III trials confirms the importance of AR signaling in castration-resistant disease. Additionally, progression on these newer forms of ADT invariably occurs in the setting of a rise in serum prostate-specific antigen (PSA) level, an AR target gene, and persistent AR expression.[27] Therefore, evidence from patients confirms what preclinical experiments suggest: that AR continues to be a core driver of prostate cancer even after exposure to the highly potent agents abiraterone or enzalutamide. If we are to build on recent progress, we should strive to understand all of the mechanisms of AR-mediated resistance to therapy and seek to impede them through the development of new and better therapies, and perhaps through the development of multi-agent regimens that more completely abrogate AR signaling.

In addition to the dominant role played by the AR, trial design and scientific approach have also limited our success in advancing targeted therapy in prostate cancer. Most targeted agents perturb only one target or a handful of related targets at a time. Trials that evaluate these agents have generally been designed without a comprehensive understanding of how the cancer cell circumnavigates this single perturbation and how the normal host tissue is affected. They have also been designed without efforts to enrich study populations to include those patients whose tumors possess molecular characteristics that point towards specific targeted agents.

To improve on our track record, we need to understand the effect of our treatments on both the tumor and the host, and we need to appreciate the complexity of the tumor-host interface. Recently, for example, by examining human prostate tumors before and after chemotherapy, we identified a spectrum of proteins secreted in the tumor microenvironment. The secretion of Wnt ligand WNT16B in the tumor microenvironment was found to activate the Wnt pathway in tumor cells in a paracrine manner.[28] Wnt pathway activation, in turn, induced chemotherapy resistance in tumor cells. This is but one example of the complexity of adaptive resistance and the importance of host microenvironmental factors.

This example illustrates the point that in addition to molecular speciation of tumor cells to individualize therapy, we need to turn our attention to the host-tumor interface. To do so, we would do well to study advanced prostate cancer in its natural environment, ie, human metastases. Analysis of human metastatic CRPC tumors, as well as preclinical studies of drugs using orthotopic models and/or immunocompetent animals, are therefore essential components of successful target development.

To this end, two “Prostate Cancer Dream Teams,” funded by the Stand Up To Cancer Foundation, the Prostate Cancer Foundation, and the American Association for Cancer Research, are working to understand the drivers of lethal patient CRPC tumors by using comprehensive sequencing-based approaches to characterize human tumor specimens in the context of treatment response and resistance. It is our hope that this work will clarify the relevant resistance mechanisms and enable sophisticated, individualized cotargeting strategies, and that this work will give rise to a new era of success in the development of targeted therapy for prostate cancer.

We in the medical community have been down this road before, using an iterative approach that ultimately resulted in effective drug combinations. That is how we developed curative treatments for tuberculosis and how multi-drug cocktails have rendered HIV infection a chronic disease in much of the world. However, because of the way targeted therapies in CRPC have been historically developed and tested, we have not had the necessary knowledge to make the same strides as our infectious disease colleagues.

The German philosopher Friedrich Nietzsche is credited with the aphorism “that which does not destroy me, makes me stronger.” Nietzsche’s aphorism also applies to CRPC: Any cancer that is not cured by a treatment gains strength through surviving that treatment. We must do better. We need to understand each patient’s cancer and its microenvironment well enough to develop targeted treatments that will kill the tumor the first time-for if we let it escape, 70 years of prostate cancer research teaches us that our job will only get harder.

Financial Disclosure:Drs. Alumkal, Graff, and Beer have received research funding from Amgen, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Cougar Biotechnology, Dendreon, ImClone Systems, Janssen Pharmaceuticals, Medivation, Millennium, Novartis, OncoGeneX, and Sanofi-Aventis.

References:

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