Cancer of the Breast by DeVita Vincent T.;Lawrence Theodore S.;Rosenberg Steven A.;

Author:DeVita, Vincent T.;Lawrence, Theodore S.;Rosenberg, Steven A.;
Language: eng
Format: epub
ISBN: 9781496354150
Publisher: Wolters Kluwer
Published: 2016-03-08T00:00:00+00:00

Two hypotheses have emerged to explain the clinical activity of rapalogs in kidney cancer. The antiproliferative activity of these compounds against endothelial cells suggests an antiangiogenic mechanism, which is consistent with the clinical activity of the VEGF receptor inhibitors. But rapalogs also inhibit the growth of kidney cancer cell lines in laboratory models where the effects on tumor angiogenesis have been eliminated. Interestingly, mRNAs for HIF1/2 are among those whose translation is impaired by rapalogs, and this effect has been implicated as the primary mechanism of rapalog activity in kidney cancer xenograft models.84 As with the VEGF receptor inhibitors, a detailed molecular annotation of tumors from responders and nonresponders will shed light on these issues.

Other Indications for mTOR Inhibitors: Breast Cancer and Tuberous Sclerosis Complex Mutant Cancers

Two other indications for mTOR have emerged, both based on fundamental insights from laboratory studies but from quite different angles. Preclinical studies of estrogen receptor (ER) therapy in breast cancer suggested that phosphatidylinositol 3-kinase (PI3K) pathway activation may be a mechanism of resistance and that this resistance could be prevented or overcome by combined treatment with ER-based drugs and rapalogs such as everolimus. Based on evidence that some women with progressive disease while receiving the aromatase inhibitor letrozole have clinical benefit from the addition of everolimus, randomized trials were initiated comparing everolimus + exemestane to exemestane alone (called BOLERO-2), or everolimus + tamoxifen to tamoxifen alone (called TAMRAD). Both studies demonstrated substantial improvements in time to progression in women with metastatic breast cancer who had already failed one aromatase inhibitor,85,86 resulting in FDA approval of the everolimus/exemestane combination. Evidence of cross-talk between the PI3K pathway and hormone receptor signaling (ER in breast cancer, androgen receptor in prostate cancer) provides a molecular rationale for the clinical benefit of combination therapy and is currently under investigation in metastatic prostate cancer.87

Yet another indication for rapalog therapy emerged from the genetics of children with tuberous sclerosis caused by a loss of function mutations in tuberous sclerosis complex 1 (TSC1) or TSC2, which encode the proteins hamartin and tuberin that function in the PI3K signaling pathway just upstream of mTOR. Based on laboratory studies showing that TSC1- or TSC2-deficient cells are exquisitely sensitive to rapalogs, a clinical trial was conducted in tuberous sclerosis patients with benign subependymal giant-cell astrocytomas (SEGA) that showed tumor shrinkage in 21 of 28 patients.88 This genetic dependence on mTOR in tumors with tuberous sclerosis complex (TSC) loss has also been observed in bladder cancer. In a remarkable example of the power of comprehensive DNA sequencing to provide insight into rare clinical phenotypes, investigators examined the tumor genome of the single complete responder patient on a phase II trial of everolimus in bladder cancer and discovered somatic mutations in TSC2 as well as a second gene, NF2, that also controls mTOR activity.89 This plus other examples of how a retrospective genomic analysis of extraordinary responders has led to a national effort to capture these cases, as well as prospective clinical trials of patients with the relevant tumor genotype regardless of histology (called basket trials).

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