Abstract IA26: Role of the microenvironment in prostate cancer progression and resistance
Authors: Logothetis Christopher J. 
Published: May 2013

Abstract
The improved understanding of prostate cancer progression and resistance has led to the development and application of therapies that have prolonged the survival of patients with advanced cancer. These therapies have been based on newly identified mechanisms of microtubule poisons, tumor-associated bone microenvironment, and an appreciation that the transition from endocrine to intracrine (autocrine/paracrine) androgen signaling is implicated in castrate resistance (Geller et al, Nelson et al). Investigators have hypothesized that the efficacy of microtubule poisons has been in part attributed to their ability to interrupt androgen signaling in prostate cancer (Gianakakou et al, Kyprianou et al). The role of Src family kinases, RANKL, and FGF, as well as the recent observation that C-met/VEGR 2 inhibitor may alter the progression of bone metastases, provide confidence in the relevance of experimental observations to human prostate cancer (Gallick et al, Fizzazi et al, Navone et al). Furthermore, the perplexing finding that PSMA and PSA vaccines prolong the survival of patients with prostate cancer without causing objective responses or measurably delaying time to progression add to the enthusiasm for the outcome, but have created new challenges (Kantoff et al).
Evidence that individual agents with diverse mechanisms prolong survival is encouraging; however, most patients experience disease progression. This has provided the impetus for understanding mechanism(s) of resistance and the interaction between interventions. Development of predictive markers based on the understanding of the mechanisms of response and resistance will form the foundation for a marker-driven combinatorial treatment strategy.
Recent advances in the ability to sample prostate cancer tissue at metastatic sites and to develop tumor grafts have partially overcome the limitations of previous model systems and the difficulties of accessing relevant tumor samples (Navone et al, Efstathiou et al). These tools have been used to identify subsets of cancers driven by biologically relevant differences (Aparicio et al). Identification of aggressive variants of prostate cancer in clinical and murine systems have led to prioritization and development of cyclin-dependent and Aurora kinases as targets for this subset of patients (Beltran et al, Sankar et al, Tzelepi et al). Furthermore, the characterization of cancers in model systems and clinically while on treatment with the potent antiandrogen MDV 3100 and the androgen biosynthesis inhibitor abiraterone acetate have identified CYP 17 expression, presence of steroid hormones at picogram levels, and intense nuclear AR expression as components of a predictive signature. If validated, the signature may be used to identify subsets of patients likely to benefit from further modulation of AR signaling.
Trial designs that account for the complex therapeutic environment in which drugs are delivered have been developed, deployed, and their feasibility established (Thall et al , Millikan et al). Incorporating the coclinical trials strategy promises to accelerate development of combinatorial treatment (Pandolfi et al). Taken together, advances in the basic understanding of cancer progression and resistance, new agent development, modeling, and improved trial design establish a foundation for effective marker-driven therapy that optimally integrates microenvironment-targeted therapies, immunotherapy, and microtubule poisons for patients with advanced prostate cancer.
Citation Format: Christopher J. Logothetis. Role of the microenvironment in prostate cancer progression and resistance [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA26.