Pertinent examples include:
Malignant melanoma is characterized by frequent loss of cell- cycle regulatory factors and derangement of cell-cycle checkpoints. CTEP is testing the potent cyclin-dependent kinase (cdk) inhibitor SCH727965 in melanoma, which is driven by the microphthalmia associated transcription factor (MiTF) that regulates cdk2 in a melanocyte-specific fashion.
Although infrequent (< 20%), c-KIT mutations and amplifications have been observed almost entirely in patients with mucosal or acral melanoma , and occasionally chronic sun-damaged melanoma. To test the hypothesis that melanomas characterized by mutations or amplifications of c-KIT would respond to therapy with c-KIT inhibition, a phase 2 multi-center study of imatinib was initiated in patients selected for the presence of a mutation or amplification of c-KIT. Preliminary findings indicate that nearly all patients with c-KIT mutation or amplification experienced a tumor response. While these findings need to be extended and confirmed, they provide encouraging support for a patient-tailored treatment approach.
CTEP’s new initiative for targeting cancer-initiating cells (also referred to as cancer stem cells) is testing strategies to block dysregulated embryonic signaling in cancer cells. GDC-0449 (Roche), a smoothened (SMO) inhibitor, is being studied by the Adult Brain Tumor Consortium (ABTC) in glioblastoma (GBM) to determine whether the eradication of GBM cancer-initiating cells, in which self-renewal and proliferation may be driven by Hedgehog signaling activation, may result in improved patient outcome. In addition, GDC-0449 may hold promise in adult and pediatric medulloblastomas, where mutation-driven dysregulated Hedgehog signaling occurs. A retrospective analysis of patients’ paraffin embedded tumors for SMO will be correlated with the response to GDC-0449 treatment. RO4929097, a pan Notch-signaling inhibitor is another novel small molecule with potential clinical activity in melanoma. There are three melanoma studies to test the hypothesis that melanoma initiating stem cells are dependent on Notch signaling for self-renewal and survival.