A Phase II, Randomized, Placebo-Controlled Study of Vismodegib as Maintenance Therapy in Patients with Ovarian Cancer in Second or Third Complete Remission

Drug Devlopment Unit, The Royal Marsden Hospital.
Clinical Cancer Research (Impact Factor: 8.72). 10/2012; 18(23). DOI: 10.1158/1078-0432.CCR-12-1796
Source: PubMed


Hedgehog pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor-stromal interactions. Vismodegib is an orally available Hedgehog pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR).

Experimental design:
Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).

One hundred four patients were randomized to vismodegib (n = 52) or placebo (n = 52); median PFS was 7.5 months and 5.8 months, respectively [HR 0.79; 95% confidence interval (CI), 0.46-1.35]. The HR was 0.66 (95% CI, 0.36-1.20) for second CR patients (n = 84) and 1.79 (95% CI, 0.50-6.48) for third CR patients (n = 20). The most common adverse events in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues.

In this study, the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hedgehog ligand expression was lower than expected.

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    • "Several other small-molecule inhibitors such as LDE225 and IPI-926 (Saridegib) are also being evaluated in clinical trials (Low and de Sauvage, 2010). It merits mentioning that all of these drugs target SMO and, to date, appear to be largely ineffective in solid tumors other than BCC (Kaye et al., 2012). Our study demonstrates that FOXC1 activates Hh signaling independently of SMO and thereby induces resistance to SMO inhibitors in BLBC cells. "
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    ABSTRACT: The mesoderm- and epithelial-mesenchymal transition-associated transcription factor FOXC1 is specifically overexpressed in basal-like breast cancer (BLBC), but its biochemical function is not understood. Here we demonstrate that FOXC1 controls cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Hedgehog (Hh) signaling. This non-canonical activation of Hh is specifically mediated by Gli2. We further show that the N-terminal domain of FOXC1 (aa 1-68) binds directly to an internal region (aa 898-1168) of Gli2, enhancing the DNA-binding and transcription-activating capacity of Gli2. FOXC1 expression correlates with that of Gli2 and its targets in human breast cancers. Moreover, FOXC1 overexpression reduces sensitivity to anti-Hedgehog (Hh) inhibitors in BLBC cells and xenograft tumors. Together, these findings reveal FOXC1-mediated non-canonical Hh signaling that determines the BLBC stem-like phenotype and anti-Hh sensitivity, supporting inhibition of FOXC1 pathways as potential approaches for improving BLBC treatment.
    Full-text · Article · Nov 2015 · Cell Reports
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    • "Importantly, a clinical trial using GDC-0049 (Vismodegib), a small-molecule inhibitor of Smo, recently carried out in patients with epithelial ovarian cancer in second or third remission, did not show any increase in progression-free survival for vismodegib maintenance versus placebo. Noteworthy, there was a lower than expected prevalence of Hedgehog ligand expression in archival tumor tissue, and thus a correlation between Hedgehog ligand expression and clinical benefit could not be determined [40]. Altogether, these findings further strength the idea that for accurately testing future tumor therapies involving Hh pathway inhibitors, efforts have to be made to make sure to select experimental models that best represent human tumor. "
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    ABSTRACT: Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, glioblastoma, melanoma as well as pancreas, colorectal, and prostate carcinomas. Here we investigated the role of the transcription factor Gli1 in ovarian cancer. To this end, the expression profile of Gli1 was examined in normal ovaries, ovarian tumors, and ovarian cancer cell lines, and the in vitro effects of a specific Hh-pathway blocker, KAAD-cyclopamine, or a specific Gli1 inhibitor (GANT58) on cell proliferation and on Hh target gene expression were also assessed. Results obtained showed that epithelial cells in ovarian cancer tissue express significantly higher levels of nuclear Gli1 than in normal ovarian tissue, where the protein was almost undetectable. In addition, multivariate analysis showed that nuclear Gli1 was independently associated to poor survival in advanced serous ovarian cancer patients (HR = 2.2, 95%CI 1.0-5.1, p = 0.04). In vitro experiments demonstrated Gli1 expression in the three ovarian carcinoma cell lines tested, A2780, SKOV-3 and OVCAR-3. Remarkably, although KAAD-cyclopamine led to decreased cell proliferation, this treatment did not inhibit hedgehog target gene expression in any of the three ovarian cancer cell lines, suggesting that the inhibition of cell proliferation was a nonspecific or toxic effect. In line with these data, no differences on cell proliferation were observed when cell lines were treated with GANT58. Overall, our clinical data support the role of Gli1 as a prognostic marker in advanced serous ovarian cancer and as a possible therapeutic target in this disease. However, our in vitro findings draw attention to the need for selection of appropriate experimental models that accurately represent human tumor for testing future therapies involving Hh pathway inhibitors.
    Full-text · Article · Mar 2013 · PLoS ONE
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    ABSTRACT: Increasing evidence points to an uncommon cellular population endowed of functional properties of adult stem cells, and commonly referred to as cancer stem cells (CSC), as responsible for tumor initiation and propagation. CSC have been isolated and characterized in many human solid tumors and hematological malignancies, and have been found in commercial cell lines. It is now evident that this cellular fraction is reminiscent of its origin of which retains key traits, even including a multifaceted defensive machinery that allow adults stem cells to survive cytotoxic injuries. Consistent with this, CSC aberrantly activate DNA repair pathways to remove damage induced by alkylating agents or ionizing radiation, and are characterized by high expression of multidrug resistance pumps able to actively extrude many chemotherapeutic agents. Moreover, microenvironmental stimuli seem to confer stem-like features to cancer cells, thus probably representing an indirect mechanism of chemoresistance. Like adult stem cells, CSC rely for survival and expansion on dedicated pathways connected with the self-renewal program. Different self-renewal pathway antagonists have demonstrated anti-CSC activity in preclinical models and many of these compounds are undergoing clinical development.
    No preview · Chapter · Jan 2012
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