Abstract LB-1: An investigator-initiated, phase II randomized, double-blind, placebo-controlled trial of GDC-0449 for prevention of BCCs in basal cell nevus syndrome (BCNS) patients.gg

Tang, Jean Y.; Mackay‐Wiggan, Julian; Aszterbaum, Michelle; Lindgren, Joselyn; Chang, Kris S.; Coppola, Carol; Campbell, Angela; Chanana, Anita M.; Marji, Jackleen; Callahan, Chris; Yauch, Robert L.; Bickers, David R.; Epstein, Ervin

doi:10.1158/1538-7445.am2011-lb-1

Cited by 12 publications

(4 citation statements)

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“…This randomized, double-blind, placebo-controlled trial was designed to evaluate the efficacy of vismodegib in preventing the development of new BCC. The data safety monitoring board discontinued the placebo arm due to statistically significant differences in the number of new BCC (0.07 new BCC/month in treated patients vs 1.74 new BCC/month for those on placebo) and the change in size of existing BCC (decrease of 24 cm in vismodegib arm vs −3 cm in placebo arm) 93. The 2011 ASCO Annual Meeting featured two reports on vismodegib in combination with chemotherapy.…”

Section: Targeting Hh Signaling In Cancermentioning

confidence: 99%

“…The data safety monitoring board discontinued the placebo arm due to statistically significant differences in the number of new BCC (0.07 new BCC/month in treated patients vs 1.74 new BCC/month for those on placebo) and the change in size of existing BCC (decrease of 24 cm in vismodegib arm vs −3 cm in placebo arm). 93 The 2011 ASCO Annual Meeting featured two reports on vismodegib in combination with chemotherapy. A Phase I trial examined the combination of vismodegib with erlotinib and gemcitabine for unresectable pancreatic cancer.…”

Section: Targeting Hh Signaling In Cancermentioning

confidence: 99%

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Hedgehog pathway as a drug target: Smoothened inhibitors in development

Lin¹,

Matsui²

2012

OTT

131

114

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Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian), the transmembrane receptor Patched, the signal transducer Smoothened (Smo), and transcription factors Gli1–3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells) have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain for appropriate patient selection and the optimal combination and sequence of these targeted therapies into current treatment paradigms.

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Section: Targeting Hh Signaling In Cancermentioning

confidence: 99%

Section: Targeting Hh Signaling In Cancermentioning

confidence: 99%

Hedgehog pathway as a drug target: Smoothened inhibitors in development

Lin¹,

Matsui²

2012

OTT

131

114

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“…Basal cell skin cancer, the most common cancer in humans, results largely from mutations in hedgehog pathway genes, including the protein patched homolog 1 (PTCH1) gene, which constitutively activates smoothened (SMO) during progression to basal cell cancer. The oral, highly specific small-molecule SMO inhibitor GDC-0449 first produced remarkable clinical responses (response rate of 50%) in advanced metastatic basal cell carcinoma (31) and then nearly completely suppressed basal cell lesions (P < 0.001) in a very recent double-blind, placebo-controlled randomized prevention trial in 41 very high-risk Gorlin syndrome patients, who have a germ line PTCH1 mutation; patients were randomly assigned in a drug-to-placebo ratio of 2 to 1 (32). GDC-0449 also reduced the downstream hedgehog signaling target Gli1 mRNA levels by 200-fold.…”

Section: Cancer/ Therapymentioning

confidence: 99%

Cancer Interception

Blackburn

2011

Cancer Prevention Research

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A common perception is that cancer risk reduction is passive, such as not smoking. However, advances in the understanding of cancer biology and in cancer treatment modalities suggest that it is now timely to consider anew cancer risk reduction by active, including pharmacologic, approaches. Risk avoidance approaches are certainly important, but other approaches are important as well, as exemplified by the irony that most new lung cancers occur in former smokers, or current avoiders. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. A great challenge is to educate people that the development of cancers, like heart disease, typically takes years and accordingly can potentially be intercepted with risk-reducing agents in the same way that advanced cancers can be treated with drugs or that cardiovascular disease can be intercepted with antihypertensive and other risk-reducing drugs. The cancer biology behind cancer interception is increasingly solid. For example, hedgehog pathway studies of mutations in the patched homolog 1 (PTCH1) gene, which constitutively activates Smoothened (SMO), led to development of an oral SMO inhibitor active in advanced basal cell carcinoma and which, in very high-risk Gorlin syndrome patients (germ line PTCH1 mutation), is nearly completely clinically effective in intercepting basal cell neoplasia. Also, the oral immunomodulator lenalidomide, first found to be active in advanced, relapsed multiple myeloma, was highly effective in intercepting the precursor stage, high-risk smoldering multiple myeloma from progressing. These are but two exciting, recent examples of the many advances in cancer research that have created an optimal time to discover and implement cancer interception. The multifaceted roles of telomere maintenance in both fueling advanced cancers and, at early stages, keeping them at bay, also highlight how the growing knowledge of cancer biology opens avenues for cancer interception. Emerging molecular techniques, including next-generation sequencing platforms, that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. Keeping the medical community and public at large informed about possibilities for actively intercepting cancer will be important for gaining acceptance of this increasingly powerful approach to lessening the cancer burden. Cancer Prev Res; 4(6); 787-92. Ó2011 AACR.

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“…In multiple myeloma, lenalidomide, an immunomodulating agent, is an effective treatment [74] and is also being studied for use in smoldering myeloma, the precursor stage to this malignancy. For patients with metastatic basal cell carcinoma, a hedgehog inhibitor, GDC-0449, can result in impressive responses [75]; for patients with Gorlin's syndrome, who are genetically predisposed to basal cell carcinoma, this same hedgehog inhibitor can suppress development of cancer [76]. As in breast cancer, antihormonal agents are effective for prostate cancer in the settings of advanced malignancy [77], localized disease [78], and chemoprevention [27].…”

Section: Personalizing Prevention Of Lung Cancermentioning

confidence: 99%

Personalizing Lung Cancer Prevention Through a Reverse Migration Strategy

Gold

Kim

Wistuba

et al. 2012

Natural Products in Cancer Prevention and Therapy

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Lung cancer is the deadliest cancer in the United States and worldwide. Tobacco use is the one of the primary causes of lung cancer and smoking cessation is an important step towards prevention, but patients who have quit smoking remain at risk for lung cancer. Finding pharmacologic agents to prevent lung cancer could potentially save many lives. Unfortunately, despite extensive research, there are no known effective chemoprevention agents for lung cancer. Clinical trials in the past, using agents without a clear target in an unselected population, have shown pharmacologic interventions to be ineffective or even harmful. We propose a new approach to drug development in the chemoprevention setting: reverse migration, that is, drawing on our experience in the treatment of advanced cancer to bring agents, biomarkers, and study designs into the prevention setting. By identifying molecular drivers of lung neoplasia and using matched targeted agents, we hope to personalize therapy to each individual to develop more effective, tolerable chemo-prevention. Also, advances in risk modeling, using not only clinical characteristics but also biomarkers, may help us to select patients better for chemoprevention efforts, thus sparing patients at low risk for cancer the potential toxicities of treatment. Our institution has experience with biomarker-driven clinical trials, as in the recently reported Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, and we now propose to bring this trial design into the prevention setting.

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Abstract LB-1: An investigator-initiated, phase II randomized, double-blind, placebo-controlled trial of GDC-0449 for prevention of BCCs in basal cell nevus syndrome (BCNS) patients.gg

Cited by 12 publications

References 0 publications

Hedgehog pathway as a drug target: Smoothened inhibitors in development

Hedgehog pathway as a drug target: Smoothened inhibitors in development

Cancer Interception

Personalizing Lung Cancer Prevention Through a Reverse Migration Strategy

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