Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.

https://downloads.hindawi.com/journals/pc/2013/981684.pdf

Emerging Molecularly Targeted Therapies in Castration Refractory Prostate Cancer

The PI3K/AKT/mTOR pathway is one of the most frequently altered pathways in human cancers. Although the loss of function of PTEN in prostate cancer increases the activity of the PI3K/AKT/mTOR pathway, clinical studies thus far have been disappointing. Studies of the mammalian target of rapamycin (mTOR) inhibitors rapamycin, everolimus, and temsirolimus when used as single-agents failed to demonstrate significant clinical activity in metastatic castration-resistant prostate cancer (CRPC) patients. Novel inhibitors of this pathway such as dual inhibitors of the phosphatidylinositol 3-kinase (PI3K) and mTOR pathway are now in clinical development. The most promising future use of these agents will likely be in combination with other agents such as potent AR pathway inhibitors.

Targeting the PI3K/AKT/mTOR Pathway in Prostate Cancer

Treatments that target the androgen axis represent an effective strategy for patients with advanced prostate cancer, but the disease remains incurable and new therapeutic approaches are necessary. Significant advances have recently occurred in our understanding of the growth factor and signaling pathways that are active in prostate cancer. In conjunction with this, many new targeted therapies with sound preclinical rationale have entered clinical development and are being tested in men with castration-resistant prostate cancer. Some of the most relevant pathways currently being exploited for therapeutic gain are HGF/c-Met signaling, the PI3K/AKT/mTOR pathway, Hedgehog signaling, the endothelin axis, Src kinase signaling, the IGF pathway, and angiogenesis. Here, we summarize the biological basis for the use of selected targeted agents and the results from available clinical trials of these drugs in men with prostate cancer.

https://www.ibyme.org.ar/archivos/capacitacion/t2-review.pdf

Growth factor and signaling pathways and their relevance to prostate cancer therapeutics.

250 Background: Mechanisms of resistance to docetaxel (D) are not fully understood. Preclinical work showed that administration of temsirolimus (T) between courses of D delays the growth of PTEN deficient tumors in xenografts. (Wu et al. Cancer Res 2005) The current study aims to determine the recommended phase II dose (RPTD), toxicity, pharmacokinetics (PK) and preliminary activity of D in combination with T in CRPC patients (pts). Methods: Pts aged ≥ 18 with advanced solid tumors refractory to standard therapy, ECOG ≤2, adequate bone marrow and renal function were eligible. D was given once q. 3 weeks along with T on days 2, 9 &16. The protocol was later amended and day 9 of T omitted due to excessive myelotoxicity. A 3+3 rule dose escalation was used with the next dose levels (DL) planned: DL1: D 50mg/m2, T 15 mg; DL2: D 65mg/m2, T 15 mg; DL3: D 75mg/m2, T 15 mg; DL4: D 75mg/m2, T 25 mg. An expanded cohort for pts with CRPC who have progressed to D will enroll pts once the RPTD has been defined. Result...

Overcoming docetaxel resistance in advanced castration-resistant prostate cancer (CRPC): A phase I/II trial of the combination of temsirolimus and docetaxel.

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Overcoming docetaxel resistance in advanced castration-resistant prostate cancer (CRPC): A phase I/II trial of the combination of temsirolimus and docetaxel.