CRPC oporny na leczenie z zastosowaniem ARAT (ang.)

CRPC oporny na leczenie z zastosowaniem ARAT (ang.)

Nieprzeczytany postautor: zosia bluszcz » 10 lis 2018, 02:22

Niezmiernie interesujący artykul japonskich autorow omawiający problem CRPC opornego (pierwotnie i wtornie) na leczenie z zastosowaniem antyandrogenow drugiej generacji (ARAT), ze szczegolnym uwzglednieniem zjawiska heterogenicznosci - im dluzej trwa leczenie przy pomocy ADT, tym bardziej rak staje sie heterogeniczny, zarowno w ramach pierwotnego guza jak i przerzutow, a co za tym idzie, trudniejszy do opanowania.

Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents: Opportunities and Challenges

Copyright © 2018 by authors:
Yuki Kita, Takayuki Goto, Shusuke Akamatsu, Toshinari Yamasaki, Takahiro Inoue, Osamu Ogawa,* and Takashi Kobayashi

1. Introduction
In the United States, prostate cancer (PC) is the most commonly diagnosed malignancy, and the second highest cause of cancer-related deaths among men. It is estimated that 164,690 new cases of PC will be diagnosed and 29,430 patients will die of PC in 2018 [1].
PC is dependent on androgen receptor (AR) activity for its initiation and progression.
The standard treatment for advanced PC is androgen-deprivation therapy (ADT), which suppresses the transcriptional activity of the AR.
Most tumors initially shrink in response to ADT, but eventually become castration-resistant.

In recent years, castration-resistant PC (CRPC) was shown to remain dependent on the AR signaling axis despite systemic depletion of androgens by various mechanisms [2].
Two novel agents, abiraterone and enzalutamide, were developed as second-generation AR axis-targeted (ARAT) agents that provide more potent inhibition of the AR pathway.

Abiraterone acetate is an oral drug that selectively and irreversibly inhibits the CYP17A1 microsomal enzyme, leading to inhibition of testosterone biosynthesis in the testes, adrenal glands, and PC cells.
Enzalutamide is an oral AR antagonist with eight-fold higher affinity for its target than bicalutamide [3], and also prevents AR nuclear translocation and DNA binding.
These drugs have been approved by the US Food and Drug Administration (FDA) for clinical use because they showed significant survival benefits in both docetaxel-resistant [4,5,6] and docetaxel-naïve [7,8] settings.

Despite the significant survival benefits for treatment groups compared with placebo groups, some individuals fail to respond to these drugs from the beginning of treatment (e.g., no initial prostate-specific antigen (PSA) response) because of intrinsic resistance. Although the remaining patients initially respond to treatment, they eventually develop acquired resistance, typically within a few months.
Treatment of ARAT-refractory CRPC is a clinical challenge, because effective treatment in this setting is quite limited.

Docetaxel, cabazitaxel, sipuleucel-T, and Ra-223 are current candidates for patients with ARAT-refractory CRPC, but their survival benefits are very limited or remain unproven in a restricted sense.

Moreover, treatment with ARAT agents can significantly alter the biological characteristics of CRPC, and consequently require specific attention in the management of ARAT-refractory CRPC.

This article reviews the current understanding of the molecular bases underlying intrinsic and acquired resistances to second-generation ARAT agents, focusing on their relationships with the AR signaling axis, and summarizes novel treatment strategies based on these mechanisms.


3. Next-Generation ARAT Agents

Table 1
Novel AR-targeted drugs in clinical trials.

AgentsMechanism of ActionClinical Trials
Apalutamide (ARN-509)Second-generation AR antagonistNCT01946204 (SPARTAN trial)
Darolutamide (ODM-201)Second-generation AR antagonistNCT02200614
TRC253Second-generation AR antagonistNCT02987829
Seviteronel (VT-464)Lyase-selective inhibitor of CYP17A1NCT02130700NCT02445976
Galeterone (TOK-001)Dual CYP17 inhibitor and AR antagonistNCT02438007
EPI-506N-terminal domain AR inhibitorNCT02606123


4.4. Heterogeneity Is Multi-Dimensional

Despite the increasing number of treatments proven to prolong overall survival, none of them have shown promising results in terms of a cure.
One of the main reasons for this appears to lie in the associated heterogeneity.
There are multi-dimensional classes for tumor heterogeneity including four types of diversity (Figure 2).
Tumor cells may develop intrinsic adaptations driven by multiple drivers during their progression in response to microenvironmental changes or therapeutic pressure.
An adaptation pathway via reciprocal feedback activation of PI3K signaling upon blockade of AR signaling is a typical example [55].
At the same time, another dimension of divergence may evolve within growing tumor foci (intra-tumoral heterogeneity).
When the disease has disseminated, diversity among the primary and metastatic lesions also exists (inter-tumoral heterogeneity).
In addition, CRPC cells can modify themselves over time with treatment, as represented by lineage plasticity (metachronous heterogeneity).
These heterogeneities are considered to form the basis of resistance.

Heterogenicznosc raka prostaty - przyczyną opornosci na leczenie.jpg

Figure 2
Multi-dimensional classes for tumor heterogeneity, including four types of diversity: (A) intra-tumoral, (B) inter-tumoral, and (C) metachronous heterogeneity. Tumors with different colors represent different clonalities or biological properties.

4.5. Overcoming Heterogeneity that Drives Treatment Resistance

The pivotal mechanisms associated with treatment resistance of metastatic CRPC are clearly inter-tumoral and metachronous heterogeneities.
It seems very difficult, at least to date, to treat such cases once the disease has acquired these high extents of heterogeneity and plasticity, although recent reports have shown promising results for reversing neuroendocrine differentiation of CRPC

In this regard, it appears more efficient to invest in potent treatments at earlier stages before the extent of tumor heterogeneity can become exponentially increased according to disease progression.

In the treatment-naïve state, intra-tumoral heterogeneity increases as the tumor burden increases, and individual metastatic lesions are affected by their local microenvironment to acquire further inter-tumoral heterogeneity, even though they are relatively homogeneous at the genetic level (Figure 3A).

Furthermore, the metachronous heterogeneity increases based on the plasticity induced by ADT and subsequent treatment (Figure 3B).
Therefore, a reasonable possibility to overcome such divergence-based resistance may exist in starting multiple and potent therapies targeting heterogeneous mechanisms, including adaptation pathways, at a relatively early stage when heterogeneity has not increased.
Indeed, upfront docetaxel or abiraterone in combination with ADT has shown the usefulness of early multiple treatments [87,88,89,90].

Heterogenicznosc CaP a progresja.jpg

Figure 3
Schematic illustration depicting the extent of tumor heterogeneity.
As the disease progresses in nature (A) or against therapeutic pressure (B), the extent of tumor heterogeneity is exponentially increased.

5. Conclusions
The widespread use of second-generation ARAT agents has multiplied novel biological and clinical questions, including increased tumor heterogeneity.
More effort is needed to clarify unmet clinical needs and underlying biological mechanisms, and to find a solution that can be applied to patients by frequently going back and forth between the benchside and the bedside.

Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents- Opportunities and Challenges.pdf
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