ESMO » EVENTS » MILAN 2010 ESMO CONGRESS » NEWS

10.10.10

Abnormal activation of the Hedgehog pathway is linked to tumorigenesis of a number of human malignancies. Deregulated Hedgehog signaling in tumors can be classified into two types: the first is defined by cell-autonomous mutations in key regulatory proteins, observed in basal cell carcinoma and medulloblastoma; and the second is characterized by inappropriate ligand expression and is seen in cancers of the breast, colon, prostate and pancreatic ductal adenocarcinoma. This ESMO Congress presents five reports on Hedgehog inhibition, which follow from the proof-of-concept study in basal cell carcinoma (one year ago), new observations in the pathway, evidence of acquired resistance to therapy and development of new targeted agents.

Two phase II placebo-controlled randomized studies were designed to assess efficacy and safety of GDC- 0449 (see LBAs 21 and 25) in firstline treatment of metastatic colorectal cancer, and as maintenance therapy in patients with ovarian cancer in second or third complete remission. In both settings, results do not demonstrate a clinical benefit and early drug discontinuation due to adverse events may suggest a lower tolerance in the maintenance setting. Another potent, selective Hedgehog inhibitor, LDE225 (see abstract 502PD), has been assessed in the "first-in-human study" with observed good tolerance, a favorable PK profile and target modulation. An anti-tumor response was noted in patients with recurrent medulloblastoma, and disease stabilization in patients with basal cell carcinoma, spindle cell and osteosarcoma. A report of the first clinical experience of IPI- 926 (see abstract 501PD) shows preliminary evidence of clinical activity in patients with basal cell carcinoma, medulloblastoma and chondrosarcoma. In addition, a small preclinical study shows heterogeneous expression patterns of the Hedgehog pathway in biliary tract cancer cell lines (see abstract 95P). Even though markers predicting the efficiency of pathway inhibition are yet to be identified, such an approach may prove valid for novel treatment strategies in these difficult to treat cancers. Most of the currently active pancreatic cancer studies are recruiting well.