New Research on Signal Transduction Pathways in Prostate Cancer Reveals Potential Clinical Implications

New Research on Signal Transduction Pathways in Prostate Cancer Reveals Potential Clinical Implications

Three translational studies presented at a Clinical Science Symposium on Saturday illuminate new variations in signal transduction pathways that may have far-reaching implications for clinical practice in the future. The research presented during “Signal Transduction Pathways in Prostate Cancer” concentrated on the PTEN/Akt/mTOR pathway and the TMPRSS2-ERG gene fusion in primary cancer risk, and on intratumoral androgen synthesis and upregulation of androgen receptor in metastatic prostate cancer.

In a small pharmacodynamic study of pre-prostatectomy rapamycin treatment in 32 men with advanced localized prostate cancer, a maximum tolerated dose of 3 mg per day for 14 days prior to radical prostatectomy was observed to induce higher concentrations of the agent in prostate tissue than in whole blood in ranges of 7.1 to 47.2 ng/g and 3.2 to 19.2 ng/mL. A median decline of 60% from baseline in tumor p-S6 inhibition was observed in more than half of patients with no negative effect on Akt phosphorylation.

Despite these findings presented by George Netto, MD, of Johns Hopkins University, the role of mTOR (mammalian target of rapamycin) inhibition in prostate cancer and in some other malignancies characterized by PTEN deletion remain controversial; therefore, treatment with rapamycin remains controversial as well. In his discussion of Dr. Netto’s presentation, Neal Rosen, MD, PhD, of Memorial Sloan-Kettering Cancer Center, characterized rapamycin’s role as “marginal at best.” Agreeing that inhibition of the PTEN tumor suppressor gene in the initial stages of signal transduction is the activating mechanism for enabling the mTOR oncogene downstream, he noted that rapamycin inhibits only one of two mTOR pathways. Conse- quently, although p-S6 inhibition may occur along one pathway, where there is no evidence that inhibition translates to decreased cell proliferation, Akt signaling may actually be enhanced through a feedback mechanism, leading to more mTOR oncoprotein. This limitation of rapamycin-like agents may explain why clinical trials in prostate cancer have yielded only slight improvements on overall survival. “Dual mTOR inhibitors alone or in combination with mTOR kinase inhibitors may address these deficiencies in the future,” Dr. Rosen concluded.

Among approximately 15 gene fusions identified thus far in prostate cancer, one that has been found in more than 50% of tumors is the Met160Val single nucleotide polymorphism (SNP) in the oncogenic TMPRSS2-ERG fusion. The Prostate Cancer Risk Assessment Program (PRAP) at the Fox Chase Cancer Center, has been investigating the role of this SNP in malignant transformation of the prostate in high-risk men. The study, presented by Veda N. Giri, MD, involved 231 white men with family histories of prostate cancer and 400 black men with or without family histories.

The onset of prostate cancer was significantly more rapid after at least one follow-up examination among white men with the CT/TT genotype of Met160Val compared with those with the CC genotype (p = 0.0058). The hazard ratio for prostate cancer associated with the CT/TT genotype was 2.55 compared with the CC genotype (p = 0.022). These findings suggest that the T-allele of the Met160Val variant in the TMPRSS2-ERG gene may be useful in assessing the probable time to cancer diagnosis in high-risk white men.

Although there was no significant difference in genotype distribution between white and black men, no patterns in time to disease onset or hazard ratio were observed for the latter. However, a family history of prostate cancer was not an inclusion criterion for the black population; and in the absence of a subset analysis, there is no indication of a correlation between familial and genotypic patterns.

A study conducted by the Prostate Cancer Genome Group and reported by Nicholas Mitsiades, MD, PhD, of Memorial Sloan-Kettering Cancer Center, confirms and partially quantifies some of the factors leading to intratumoral steroidogenesis in castration-resistant metastatic prostate cancer. In the study, gene expression profiles from 29 normal prostate tissue samples, 112 primary prostate carcinomas, and 19 metastatic prostate tumors were compared with 40 mRNAs encoding androgen receptors, 28 enzymes involved in androgen synthesis, and 10 enzymes involved in androgen inactivation.

Metastatic tumors expressed higher average transcript levels of androgen receptor and several steroidogenic enzymes than both normal tissue and primary tumors. Conversely, expression of the androgen inactivator mRNAs was lower in both primary and metastatic tumors than in normal tissue. In an analysis involving androgen receptor and 28 steroidogenic transcripts in individual tumors, all metastatic cancers expressed at least one transcript (range, 2 to 14; median, 5) compared with normal tissue; 76% of primary lesions overexpressed at least one transcript (range, 2 to 66; median, 2).

The findings of this study appear to validate two current trends in drug development to battle metastatic prostate cancers: novel antiandrogens such as MDV3100, and CYP17 inhibitors such as abiraterone, both of which are in early clinical trials.