Emerging targets in the AKT pathway for treatment of androgen-independent prostatic adenocarcinoma.
Prostatic adenocarcinoma (CaP) is the most common, non-cutaneous malignancy and the second-leading cause of cancer death in men. The disease has two distinct phases: the androgen-dependent phase, which can be treated effectively with androgen ablation therapies, and the androgen-independent phase, for which there is no effective life-prolonging therapy. An estimated 32,000 men will die this year from androgen-independent, metastatic CaP. Efforts to understand the metastatic progression of CaP and the emergence of androgen-independent disease have begun to illuminate the molecular events involved. Recent work suggests that CaP progression to androgen-independent, metastatic disease involves a dampened apoptotic response, a release from the cell cycle block that initially follows androgen withdrawal and a shift from dependence on paracrine-derived growth and survival factors to autonomous production of these key proteins. Functional loss of the tumour suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) and subsequent activation of the AKT pathway, have been prominently implicated in the progression of CaP to androgen-independence. Activation of the AKT pathway can suppress the apoptotic response, undermine cell cycle control and selectively enhance the production of key growth and survival factors. Though many proteins and intracellular signalling pathways can influence these biological processes, activation of the AKT pathway may be a particularly potent signal involved in CaP progression to androgen-independence and therefore presents a series of potential targets for therapy of advanced androgen-independent CaP.
Graff
Jeremy R
JR
Cancer Division, Lilly Research Labs, Eli Lilly and Company, Lilly Corporate Centre, DC 0546, Indianapolis, IN 46285, USA. graff_jeremy@lilly.com
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt