Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial

Cosimo, Serena Di; Sathyanarayanan, Sriram; Bendell, Johanna C.; Cervantes, Andrés; Stein, Mark N.; Braña, Irene; Haines, Brian B.; Zhang, Theresa; Winter, Christopher; Jha, Sharda; Xu, Youyuan; Frazier, Jason P.; Klinghoffer, Richard A.; Leighton-Swayze, Ann; Song, Yang; Ebbinghaus, Scot; Baselga, José

doi:10.1158/1078-0432.ccr-14-0940

Cited by 49 publications

(35 citation statements)

References 33 publications

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“…However, more research is needed to confirm our findings and to explore the role of insulin signaling in breast cancer initiation and/or promotion in patients with diabetes, especially among those using insulin or insulin analogues. This observation, if confirmed, might be clinically relevant since currently the use of IGF1R and mTOR inhibitors are investigated among breast cancer patients in clinical trials [19,48,49]. IGF1R and mTOR inhibitors might interfere with glucose metabolism and iatrogenic diabetes has been reported as side effect of IGF1R inhibitors.…”

Section: Discussionmentioning

confidence: 69%

The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors

et al. 2018

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Section: Discussionmentioning

confidence: 69%

The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors

et al. 2018

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“…IGF1R has been suggested to play a role in ovarian cancer due to its upregulation after combined PI3K and mTOR inhibition (43) as well as in a range of ovarian cancer cell lines after AKT inhibition (20), but was not pursued with functional inhibitor experiments in these studies. These and other (44)(45)(46)(47) examples demonstrate that IGF1R inhibition may prove a valuable addition to inhibitors targeting the MAPK and PI3K pathways.…”

Section: Discussionmentioning

confidence: 88%

Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R

Lint

Poell

Soueidan

et al. 2016

Molecular Cancer Therapeutics

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Targeted therapies have proven invaluable in the treatment of breast cancer, as exemplified by tamoxifen treatment for hormone receptor-positive tumors and trastuzumab treatment for HER2-positive tumors. In contrast, a subset of breast cancer negative for these markers, triple-negative breast cancer (TNBC), has met limited success with pathway-targeted therapies. A large fraction of TNBCs depend on the PI3K pathway for proliferation and survival, but inhibition of PI3K alone generally has limited clinical benefit. We performed an RNAibased genetic screen in a human TNBC cell line to identify kinases whose knockdown synergizes with the PI3K inhibitor GDC-0941 (pictilisib). We discovered that knockdown of insulin-like growth factor-1 receptor (IGF1R) expression potently increased sensitivity of these cells to GDC-0941. Pharmacologic inhibition of IGF1R using OSI-906 (linsitinib) showed a strong synergy with PI3K inhibition. Furthermore, we found that the combination of GDC-0941 and OSI-906 is synergistic in 8 lines from a panel of 18 TNBC cell lines. In these cell lines, inhibition of IGF1R further decreases the activity of downstream PI3K pathway components when PI3K is inhibited. Expression analysis of the panel of TNBC cell lines indicates that the expression levels of IGF2BP3 can be used as a potential predictor for sensitivity to the PI3K/IGF1R inhibitor combination. Our data show that combination therapy consisting of PI3K and IGF1R inhibitors could be beneficial in a subset of TNBCs. Mol Cancer Ther; 15(7); 1545-56. Ó2016 AACR.

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“…The kinase mTOR (comprising mTORC1 and mTORC2) is downstream of the PI3K/AKT pathway and can be activated by mitogens, nutrients, and growth factor receptor signals [3]. mTOR plays a central role in normal cell growth and development, including a pivotal role in the development and progression of cancer, making it an attractive target for anticancer therapy [4]. …”

Section: Introductionmentioning

confidence: 99%

“…A decrease in IRS1 levels reduces IGF1R signaling and blocks activation of the PI3K pathway. Conversely, inhibition of mTORC1 prevents this negative feedback loop, resulting in sustained signaling through IGF1R/IRS1 and activation of the PI3K pathway through AKT [4, 7, 8]. Inhibiting both mTOR and IGF1R with targeted agents has been shown to result in additive or synergistic antitumor activity [4, 9].…”

Section: Introductionmentioning

confidence: 99%

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A randomized phase II trial of ridaforolimus, dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer

Rugo

Trédan

et al. 2017

Breast Cancer Res Treat

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Purpose To evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer. Methods This randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining ≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10 mg QD 5 ×/week, intravenous dalotuzumab 10 mg/kg/week, and oral exemestane 25 mg/day (R/D/E, n = 40), or ridaforolimus 30 mg QD 5 ×/week and exemestane 25 mg/day (R/E; n = 40). Primary end point was progression-free survival (PFS). Results Median PFS was 23.3 weeks for R/D/E versus 31.9 weeks for R/E (hazard ratio 1.18; 80% CI 0.81–1.72; P = 0.565). Grade 3–5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P = 0.021) and pneumonitis (22.5 vs. 5.1%; P = 0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate. Conclusions R/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

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Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial

Cited by 49 publications

References 33 publications

The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors

The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors

Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R

A randomized phase II trial of ridaforolimus, dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer

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