Medivation MDV3100 for both early-stage and advanced prostate cancer.
This is an interesting find. First, just for clarification, this is a 4 year old article and not an abstract from ASCO G/U.
The premise is that in this particular cell line, which is androgen deprivation refractory, the resistance was actually acquired by a biological pathway triggered by the androgen deprivation therapy itself which then resulted in an upregulation of cMET expression.
Some caveats have to be attached to this. First, is that this is an observation of a single cell ine and the results might not be universally applicable to all cases of CRPC. The abiraterone experience has also demonstrated that CRPC does not equal HRPC. A fairly high percentage of hormone ablation resistance is probably due to the tumor developing the ability to produce its own Androgen rather than finding an alternative growth stimulus. Though this article addresses a possible mechanism for upregulation of cMET, it doesn't address the MOA that would explain Cabo's apparent ability to address bone met activity. The final sentence of the abstract makes a great argument for a frontline Abiraterone +/- Cabo pivotal trial.
Abstract The precise molecular mechanisms by which prostate cancer cells progress from androgen-sensitive to androgen-insensitive status still remain largely unclear. The hepatocyte growth factor/scatter factor (HGF/SF) plays a critical role in the regulation of cell growth, cell motility, morphogenesis, and angiogenesis. The aberrant expression of HGF/SF and its receptor, c-Met, often correlates with poor prognosis in a variety of human malignancies, including prostate cancer. Here, we investigate a potential link between androgen signaling and c-Met expression in prostate cancer cells. First, we showed that the androgen receptor (AR) represses the expression of c-Met in a ligand-dependent manner. Using different c-Met promoter/reporter constructs, we identified that Sp1 induces the transcription of c-Met and that AR can repress the Sp1-induced transcription in prostate cancer cells. Moreover, the data from electrophoretic mobility shift assay showed that AR interferes with the interaction between Sp1 and the functional Sp1 binding site within the c-Met promoter. Furthermore, we tested the effect of AR on c-Met expression in an androgen-insensitive prostate cancer cell line, CWR22Rv1. Finally, the repressive role of androgen signaling on c-Met expression was confirmed in prostate cancer xenografts. The above data indicate a dual role of AR in transcriptional regulation. Although the current androgen ablation therapy can repress the expression of growth-promoting genes that are activated by the AR, it may also attenuate the repressive role of AR on c-Met expression. Therefore, the therapeutic strategies to inhibit the activation of the HGF/c-Met pathway may be of benefit when combined with current androgen ablation treatment. [Cancer Res 2007;67(3):967–75]