Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial

Kalinsky, Kevin; Sparano, Joseph A.; Zhong, Xiaobo; Andreopoulou, Eleni; Taback, Bret; Wiechmann, Lisa; Feldman, Sheldon; Ananthakrishnan, Preya; Ahmad, Aqeel; Cremers, Serge; Sireci, Anthony; Cross, Justin R.; Marks, Douglas K.; Mundi, Prabhjot S.; Connolly, Eileen; Crew, Katherine D.; Maurer, Matthew; Hibshoosh, Hanina; Lee, S. M.; Hershman, Dawn L.

doi:10.1007/s12094-018-1888-2

Cited by 22 publications

(19 citation statements)

References 31 publications

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“…In our preclinical work, we had shown that MK-2206 led to a dose-dependent decrease in AKT signaling in vitro and a dose-dependent decrease in tumor growth in vivo, with regression observed at higher doses that were associated with decreases in AKT signaling. These results are in line with a recent report from Kalinsky et al where they assessed MK-2206 pharmacodynamics effect in a presurgical window-of-opportunity trial in breast cancer [15]. Two doses of MK-2206 were administered, 9 and 2 days before surgery.…”

Section: Discussionsupporting

confidence: 87%

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

et al. 2019

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Background The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. Methods The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed. Results Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. Conclusions MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. Trial registration ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011. Electronic supplementary material The online version of this article (10.1186/s13058-019-1154-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 87%

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

et al. 2019

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“…PI3K/AKT/mTOR and CDK4/6 inhibitors are emerging drugs for the treatment of ER-positive and human epidermal growth factor receptor-2 (HER2) negative metastatic BC ( 95 ). The PI3K/AKT/mTOR pathway is an important oncogenic signaling pathway in BC that can be activated by hyperglycemia to promote the proliferation of malignant BC epithelial cells ( 56 , 95 ). Everolimus is an mTOR inhibitor that can target the rapamycin pathway.…”

Section: Hyperglycemia Affects Response To Therapy In Bc Patientsmentioning

confidence: 99%

Hyperglycemia and Chemoresistance in Breast Cancer: From Cellular Mechanisms to Treatment Response

2021

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Female breast cancer is a complex, multifactorial disease. Studies have shown that hyperglycemia is one of the most important contributing factors to increasing the risk of breast cancer that also has a major impact on the efficacy of chemotherapy. At the cellular level, hyperglycemia can promote the proliferation, invasion, and migration of breast cancer cells and can also induce anti-apoptotic responses to enhance the chemoresistance of tumors via abnormal glucose metabolism. In this article, we focus on the latest progress in defining the mechanisms of chemotherapy resistance in hyperglycemic patients including the abnormal behaviors of cancer cells in the hyperglycemic microenvironment and the impact of abnormal glucose metabolism on key signaling pathways. To better understand the advantages and challenges of breast cancer treatments, we explore the causes of drug resistance in hyperglycemic patients that may help to better inform the development of effective treatments.

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“…Likewise, completion of the trial testing MK-2206 plus anti-estrogen therapy for ER pos breast cancer failed to show clinical activity above that of anastrazole alone [38]. Finally, a trial using MK-2206 as a monotherapy prior to scheduled surgical resection of operable breast cancer was stopped due to unexpectedly high toxicity, given this particular clinical setting [39]. It therefore appears that MK-2206, like other Akt inhibitors currently being tested, are of unproven value therapeutically, at least as part of the therapy regimens tested up to this point.…”

Section: Discussionmentioning

confidence: 99%

Th1 cytokines in conjunction with pharmacological Akt inhibition potentiate apoptosis of breast cancer cells in vitro and suppress tumor growth in vivo

2020

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Targeted drug approaches have been a major focus for developing new anticancer therapies. Although many such agents approved in the last 20 years have improved outcomes, almost all have underperformed expectations. The full potential of such agents may yet be obtained through novel combinations. Previously, we showed that anti-estrogen drugs combined with a dendritic cell-based anti-HER-2 vaccine known to induce strong Th1-polarized immunity dramatically improved clinical response rates in patients with HER-2 pos /ER pos early breast cancer. Here, we show that the small molecule Akt antagonist MK-2206, when combined with the Th1 cytokines IFN-gamma and TNF-alpha, maximize indicators of apoptotic cell death in a panel of phenotypicallydiverse human breast cancer lines. These findings were mirrored by other, structurallyunrelated Akt-targeting drugs that work through different mechanisms. Interestingly, we found that MK-2206, as well as the other Akt antagonist drugs, also had a tendency to suppress Th1 cytokine expression in stimulated human and murine lymphocytes, potentially complicating their use in conjunction with active immunotherapy. After verifying that MK-2206 plus IFN-gamma could show similar combined effects against breast cancer lines, even in the absence of TNF-alpha, we tested in a rodent HER-2 pos breast cancer model either a HER-2-based DC vaccine, or recombinant IFN-gamma with or without MK-2206 administration. We found that for MK-2206, co-administration of recombinant IFN-gamma outperformed co-administration of DC vaccination for slowing tumor growth kinetics. These findings suggest a combined therapy approach for Akt-targeting drugs that incorporates recombinant Interferon-gamma and is potentially translatable to humans.

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Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial

Cited by 22 publications

References 31 publications

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

Hyperglycemia and Chemoresistance in Breast Cancer: From Cellular Mechanisms to Treatment Response

Th1 cytokines in conjunction with pharmacological Akt inhibition potentiate apoptosis of breast cancer cells in vitro and suppress tumor growth in vivo

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