Article

Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors

Internal Medicine, University of Michigan.
Clinical Cancer Research (Impact Factor: 8.72). 01/2013; 19(6). DOI: 10.1158/1078-0432.CCR-11-3326
Source: PubMed

ABSTRACT

Purpose:
Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy.

Experimental design:
Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies.

Results:
Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44(+)/CD24(-), ALDH(+), and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies.

Conclusions:
These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer.

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Available from: clincancerres.aacrjournals.org
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    • "We identify Hif-1a as the nonessential subunit of g-secretase that can shift and modulate enzyme equilibrium from the inactive complex to the active form. g-Secretase inhibitors (GSIs) are on trial for the treatment for a variety of neoplasms, and some clinical benefit has been observed (Gounder and Schwartz, 2012; Krop et al., 2012; Schott et al., 2013; Tolcher et al., 2012; Wei et al., 2010). Notch signaling plays an important role in cancer metastasis (Sethi and Kang, 2011), and GSI treatment reduced Notch-mediated bone metastasis of breast cancer (Sethi et al., 2011). "
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    • "Until such assays are available we will not know whether we can predict with any accuracy the differential in vivo activity of a given GSI using current preclinical models. With the repurposing of GSIs for cancer, one of the key findings from the early human trials is that subacute dosing with GSIs is reasonably well-tolerated especially when dosing regimens are altered so that dosing is not continuous but intermittent[123]. Alternatively, administration of glucocortocoids with GSI dramatically attenuated gastrointestinal toxicity[124]. "
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