gdc-0449 and Cell-Transformation--Neoplastic

The Hedgehog signaling pathway has been identified as fundamentally important to normal embryonic development in living organisms ranging from fruit flies to mammals. Postdevelopmentally, it remains active in hair and skin cells. Abnormal activation of components of the Hedgehog pathway--specifically, resulting from mutations in the Patched 1 gene--is associated with the development of basal cell carcinoma, as well as several other cancers, including medulloblastoma. Patched 1 gene mutation has also been identified as the underlying mechanism in most cases of Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome). Research that resulted in the current understanding of the Hedgehog signaling pathway, in turn, led to multiple lines of investigation to discover mechanisms for halting abnormal signaling, in the hope that agents could be developed that could beneficially stop this pathway. To date, several agents have been developed-and some are in clinical trials-that hold promise for improved nonsurgical treatments for patients with Gorlin syndrome and those with locally advanced/metastatic BCCs.

Topics: Anilides; Basal Cell Nevus Syndrome; Carcinoma, Basal Cell; Cell Transformation, Neoplastic; Hedgehog Proteins; Humans; Patched Receptors; Patched-1 Receptor; Pyridines; Receptors, Cell Surface; Signal Transduction; Skin Neoplasms

Medulloblastoma is a cancer of the cerebellum, for which there is currently no approved targeted therapy. Recent transcriptomics approaches have demonstrated that medulloblastoma is composed of molecularly distinct subgroups, one of which is characterized by activation of the Hedgehog pathway, which in mouse models is sufficient to drive medulloblastoma development. There is thus considerable interest in targeting the Hedgehog pathway for therapeutic benefit in medulloblastoma, particularly given the recent approval of the Hedgehog pathway inhibitor vismodegib for metastatic and locally advanced basal cell carcinoma. Like other molecularly targeted therapies, however, there have been reports of acquired resistance to vismodegib, driven by secondary Hedgehog pathway mutations and potentially by activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Given that acquired resistance to vismodegib may occur as a result of inappropriate PI3K pathway activation, we asked if loss of the PI3K pathway regulator, phosphatase and tensin homologue (Pten), which has been reported to occur in patients within the Hedgehog subgroup, would constitute a mechanism of innate resistance to vismodegib in Hedgehog-driven medulloblastoma. We find that Hedgehog pathway inhibition successfully restrains growth of Pten-deficient medulloblastoma in this mouse model, but does not drive tumor regression, as it does in Pten-wild-type medulloblastoma. Combined inhibition of the Hedgehog and PI3K pathways may lead to superior antitumor activity in PTEN-deficient medulloblastoma in the clinic.

Topics: Anilides; Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Cerebellar Neoplasms; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Gene Deletion; Hedgehog Proteins; Medulloblastoma; Mice; Mice, Nude; Mice, Transgenic; Pregnancy; PTEN Phosphohydrolase; Pyridines; Signal Transduction

With the incidence of nonmelanoma skin cancer on the rise, current prevention methods, such as the use of sunscreens, have yet to prove adequate to reverse this trend. There has been considerable interest in identifying compounds that will inhibit or reverse the biochemical changes required for skin cancers to develop, either by pharmacologic intervention or by dietary manipulation. By targeting different pathways identified as important in the pathogenesis of nonmelanoma skin cancers, a combination approach with multiple agents or the addition of chemopreventative agents to topical sunscreens may offer the potential for novel and synergistic therapies in treating nonmelanoma skin cancer.

Topics: Anilides; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carotenoids; Cell Transformation, Neoplastic; Cyclooxygenase 2 Inhibitors; Diet, Fat-Restricted; DNA Repair Enzymes; Eflornithine; Flavonoids; Genistein; Humans; Keratosis, Actinic; Lycopene; Phenols; Photochemotherapy; Polyphenols; Pyridines; Retinoids; Skin Neoplasms; Sunscreening Agents; Ultraviolet Rays