Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer

Abstract

Recently, many therapeutic agents for prostate cancer have been approved that target the androgen receptor and/or the prostate tumor microenvironment. Each of these therapies has modestly increased patient survival. A better understanding of when in the course of prostate cancer progression specific therapies should be applied, and of what biomarkers would indicate when resistance arises, would almost certainly improve survival due to these therapies. Thus, applying the armamentarium of therapeutic agents in the right sequences in the right combination at the right time is a major goal in prostate cancer treatment. For this to occur, an understanding of prostate cancer evolution during progression is required. In this review, we discuss the current understanding of prostate cancer progression, but challenge the prevailing view by proposing a new model of prostate cancer progression, with the goal of improving biologic classification and treatment strategies. We use this model to discuss how integrating clinical and basic understanding of prostate cancer will lead to better implementation of molecularly targeted therapeutics and improve patient survival.

Figure 1. DHT-dependent phase of PCa

In this phase of PCa, some tumors rely mainly on DHT. The source of testosterone (T) is mainly from the testis and adrenal glands provide dehydroepiandrosterone (DHEA). Testosterone and DHEA are converted to DHT by 5-alpha reductases (SRD5A) present in the prostate. AR has higher affinity for DHT than testosterone. For this reason, finasteride and dutasteride, which inhibit type 1 or both type 1 and type 2 5-alpha reductase activity, respectively, can suppress tumor development or growth, accounting for suppression of low-grade cancers, but not high-grade cancers, in a proportion of men with PCa.

Figure 2. Proposed Spiral Model for PCa progression

The model proposes three main phases in PCa progression. The first phase is the DHT-dependent phase, during which the tumor is responsive to 5-alpha reductase inhibitor treatments, as indicated by the yellow arrow on the left-hand side of the figure. When the tumor is no longer responsive to inhibitors of 5-alpha reductase, it enters the progression spiral, as marked by a broad up arrow, where multiple factors, including AR signaling changes, oncogene activation, tumor suppressor gene downregulation (not shown), and microenvironment changes, affect tumor progression. Each “turn” is defined by a predictive marker(s) that can be targeted. The pitch in each spiral reflects the duration the tumors that remain responsive to a specific therapy. The adaptive changes in tumors in response to therapy accounts for resistance, leading the tumor to progress to the next turn of the progression spiral, which signals additional alterations in the tumor and its microenvironment. Tumors in this new “turn” will require different therapeutics that specifically target the altered properties that define this turn. Markers that reflect the biology that drive each turn can be used to guide timely therapy application in anticipation of progression. Exit from the spiral occurs when a series of mutations arise, including the loss of AR, RB or p53, and upregulation of PLK1, AURKA and amplification of MYCN. At this stage, the PCa cells are no longer regulated by the microenvironment and become tumor cell autonomous, as indicated by the red arrow on the right-hand side of the figure. Targeted therapies that may affect candidates that drive turns in the spiral are indicated in the figure. Possible disease stages corresponding to the spiral are also indicated.

Figure 3. Src family kinase phosphorylation correlates with therapy resistance to androgen signaling inhibitors

By immunohistochemical staining, Src family kinase phosphorylation is higher in bone marrow biopsies of men who lack response to therapy with androgen signaling inhibitors.

Figure 4. Possible outcomes of therapeutic treatments using the Spiral model

A turn in the spiral is defined through the expression or alteration of a predictive marker. Three possible outcomes of therapeutic treatment may occur based on a predictive marker that defines a turn in the spiral. Abiraterone is used as an example. After application of abiraterone, (A) No further “turns” in the spiral occur, suggesting that the therapy may be curative. (B) The turn may be elongated, suggesting that abiraterone is effective in reducing androgen generated from Cyp17. Following the treatment, tumor adaptation may occur, leading to the next turn in the spiral. Successful application of the correct therapeutic agent at this stage of the spiral will elongate the next turn. (C) Application of targeted therapy does not have a positive therapeutic effect. This result would suggest that the tumor is in a more complex phase of the disease.