Evolving Personalized Therapy for Castration-Resistant Prostate Cancer

With advances in molecular biologic and genomic technology, detailed molecular mechanisms for development of castration-resistant prostate cancer (CRPC) have surfaced. Metastatic prostate cancer (PCa) no longer represents an end stage, with many emerging therapeutic agents approved as effective in prolonging survival of patients from either pre- or post-docetaxel stage. Given tumor heterogeneity in patients, a one-size-fits-all theory for curative therapy remains questionable. With the support of evidence from continuing clinical trials, each treatment modality has gradually been found suitable for selective best-fit patients: e.g., new androgen synthesis inhibitor arbiraterone, androgen receptor signaling inhibitor enzalutamide, sipuleucel-T immunotherapy, new taxane carbazitaxel, calcium-mimetic radium-223 radiopharmaceutical agent. Moreover, several emerging immunomodulating agents and circulating tumor cell enumeration and analysis showed promise in animal or early phase clinical trials. While the era of personalized therapy for CRPC patients is still in infancy, optimal therapeutic agents and their sequencing loom not far in the future.


Current therapeutic regimen in prostate cancer
Prostate cancer (PCa) is the lead malignancy among males in Western countries, accounting for 28% (238,590) of newly diagnosed cancers in United States in 2013 [1]. It has been the second common cause of cancer deaths in men (behind lung cancer) for two decades [1,2].
Treatment for clinically localized PCa aims at cure, typically by surgery or radiation. Emerging technologies have also been used for selected patients in low-risk PCa: e.g., high-intensity focused ultrasound (HIFU), cryotherapy, radiofrequency ablation and photodynamic therapy. For advanced PCa cases, androgen deprivation therapy (ADT) is standard treatment. The majority of advanced PCa patients respond to initial ADT temporarily but inevitably progress from androgen-dependent stage to CRPC. Effective treatment at this stage is largely limited to chemotherapy. Indeed, prior to 2010, only docetaxel chemotherapy shows survival benefit in CRPC. With the most effective standard chemotherapeutic regimens, mean increase in survival time is two months, highlighting the need for more effective treatments [3,4] Figure 1 plots common clinical course of PCa from localized stage to CRPC. Interpretation of castration resistance pathway could lead to identification of new pathway-targeted therapeutics. Incidence and mortality rates vary widely across geographic regions and ethnic groups [5]. Of note, Asians have substantially lower prevalence than African Americans and Caucasians, indicating linkage between genetic background and susceptibility [6]. Exact molecular mechanisms of prostate carcinogenesis are not fully elucidated, but it is evident that genetic factors at both germline and somatic levels play key roles in carcinogenesis. It has been increasingly recognized that cancer cells are heterogeneous within the same lesion at both genetic and epigenetic levels, which could translate into functional heterogeneity: e.g., self-renewal properties, tumor-initiating ability [7]. Significant tumor heterogeneity appears within primary and metastatic tumor lesions as well as individual cases, challenging standard approach to cancer management and highlighting the need for personalized cancer therapy.

Evolving Personalized Therapy for Castration-Resistant Prostate Cancer 2 New strategies in CRPC therapy
In the case of advanced PCa, ADT is standard treatment, which initially reduced tumor burden and prostate-specific antigen (PSA) level to low or undetectable level. Most PCa ultimately recurs despite of ADT, presenting with progressively rising of PSA level, termed CRPC.
Docetaxel was regarded as the only reasonable option before 2010.
Hence abiraterone acetate significantly prolongs overall survival of mCRPC patients, with or without previous docetaxel chemotherapy.
Enzalutamide, a novel androgen receptor signaling inhibitor, competitively inhibits binding of androgens to the androgen receptor (AR), inhibits AR nuclear translocation, and inhibits association of the AR with DNA [22]. The AFFIRM trail (A multinational phase 3, randomized double-blind, placebo-controlled efficacy and safety study of oral MDV3100 in progressive CRPC previously treated with docetaxel-based chemotherapy) confirms that enzalutamide could benefit men with post-docetaxel CRPC [15]. Enzalutamide is well-tolerated and prolongs overall survival with median survival of 18.4 months, slows disease progression, and improves quality of life in men with post-docetaxel CRPC. It reduces risk of death by 37% relative to placebo [14,15].    Exploring novel PI3K pathway inhibitors may reap therapeutic benefit [35,36].

Genetic alterations highly associated with TMPRSS2-ERG
A recent rearrangement involving the androgen-regulated TMPRSS2 and members of the ETS transcription factor family (ERG, ETV1, ETV4) has been identified in a majority of prostate cancers [27,37].  [43]. Also, ETS gene-fusion status may serve as a prospective character of androgen dependence in CRPC state [44]. As deregulated transcription factors, ETS fusions may drive PCa via induction of downstream target genes, maybe offering a target as therapeutic strategy.

Androgen receptor (AR) signaling pathway
AR signaling is essential for growth and differentiation of a normal prostate and is responsible for treatment failure in CRPC or metastatic PCa. The contribution of AR to prostate tumorigenesis and disease progression is incontrovertible. The exclusive requirement of PCa cells for AR activity is illuminated at clinic, wherein therapeutic suppression of AR signaling, typically achieved through ligand depletion and direct AR antagonists, results in PSA decline and objective tumor regressions.

Conventional therapy currently focuses on androgen-dependent activation of AR via its C-terminal ligand-binding domain (LBD).
Mechanisms of therapeutic failure include AR amplification and/or overexpression, gain-of-function AR mutations, intracrine androgen production; overexpression of AR coactivators, expression of constitutively active splice variants of AR, and ligand-independent AR activation through growth factors, cytokines, or aberrant AR phosphorylation [45]. Among AR pathway genes, the most prominent finding is a peak of copy-number gain on 8q13.3 that spans the nuclear receptor coactivator gene NCOA2 [30]. High frequency of NCOA2 gain in primary tumors plus a known role as AR coactivator [46] lends insight into how these two genes collaborate in early PCa progression by enhancing AR transcriptional output. NCOA2 functions as a driver oncogene in primary tumors by increasing AR signaling; in contrast, AR amplification is largely restricted to mCRPC and likely a mechanism of drug resistance rather than a natural step in tumor progression.
Recently developed androgen-ablative and AR antagonist strategies that achieve complete androgen ablation and sufficient suppression of

Epigenetic alterations
Epigenetics is defined as heritable changes in gene expression caused by mechanisms other than altered DNA sequence. Unlike many other genetic changes, epigenetic processes are reversible and do not change DNA sequence or quantity, though they enhance genomic instability that might lead to oncogenic activation and inactivation of tumor suppressors [52]. Covalent modification of multiple DNA sites by methylation is heritable and reversible, involved in regulating a gamut of biological processes [53]. Several classes of drugs, including inhibitors of DNA methyltransferases and HDACs, are known to modify epigenetic information in a fashion not specific to genes. AR may require HDACs for transcriptional activation; HDAC inhibitors may cooperate with AR-directed therapeutics to elicit enhanced cellular response. HDAC inhibitors show promise as therapeutic targets with potential to reverse aberrant epigenetic states associated with PCa.

Personalizing treatments with circulating tumor cells (CTCs)
CTCs appear in the bloodstream, having detached from their tumor of origin. A major cause of cancer-associated mortality is tumor metastasis, which depends on successful dissemination to the whole body, mainly through blood. Therefore, CTCs shed into vasculature and possibly on the way to potential metastatic sites arouse obvious interest. Studies in past years have shown CTCs as markers predicting cancer progression and survival in metastatic [54][55][56][57] or even early-stage cancer patients [58]. Assessment CTC using CellSearch has been cleared by the FDA as a prognostic indicator for patients with metastatic breast, prostate, and colorectal cancers [54,59]. Increasing CTC numbers correlate with aggressive disease, increased metastasis, and decreased time to relapse in CRPC [55,60,61]. CTCs could serve as a real-time monitor for progression and marker for survival and thus have potential to guide therapeutic management, indicate therapy effectiveness or necessity, even while metastases are still undetectable, and offer insights into mechanisms of drug resistance. Thus, CTCs not only could be used as a surrogate endpoint marker in clinical trials [62], but also could become a treatment target [63].

Personalized immunotherapy for PCa
The concept of immune modulation, which aims at generating a meaningful antitumor immune response, has been extensively evaluated in melanoma and renal cell carcinoma. This principle has been extended to PCa, known as slow-growing and more indolent, which can allow sufficient time for generating effective antitumor immune response.
Moreover, recent studies indicated that PCa is more immunogenic than considered earlier, with evidence of PCa-specific autoantibodies in Adverse events such as chills, fever and headache were more frequently reported in the sipuleucel-T than in the placebo group [10]. Recent studies in tumor immunology have also focused on the concept of immune checkpoints, a series of molecules that function to limit an ongoing immune response [68,70]. Most treatment regimens for advanced cancer highlight a combination of chemotherapy drugs, or concurrent radio-chemotherapy, raising a possibility that immunotherapy may need combination with conventional therapy to achieve maximal effect. Fortunately, conventional cancer treatments have immunological benefits [72], making combinatorial trials attractive. In sum, there is strong rationale for combined immunotherapies and/or combining immunotherapy with conventional therapy, but such combination increases complexity for clinical trial design; issues of dosing and sequence become a great challenge.

Conclusions and perspectives
In the past decade, cancer therapy has slowly but steadily transformed from a one-size-fits-all to a more personalized approach, each patient treated according to specific genetic defects of his/her own tumor.
Appearance of genomic technologies has now provided the means to develop data that address complexity of biologic states. Practice of cancer therapy continually faces the challenge of matching the right therapeutic regimen with the right patient at the right time, balancing relative benefit with risk to attain optimal outcome. Cases with CRPC may represent myriad heterogeneity in terms of performance, Though personalized therapy for CRPC is still in its infancy, ideal therapy tailored for individual CRPC patients continues to advance.