Marianne Melnik

MET and ERBB2 Are Coexpressed in ERBB2+ Breast Cancer and Contribute to Innate Resistance

Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2+ tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET−/ERBB2+, MET+/ERBB2−, and MET+/ERBB2+. In a MET+/ERBB2+ breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2+ breast cancers express MET and contain MET+/ERBB2+ subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance. Implications: ERBB2+ breast cancers with MET+/ERBB2+ subpopulations may have an innate resistance to ERBB2 inhibition and may benefit from combined MET and ERBB2 inhibition. Mol Cancer Res; 11(9); 1112–21. ©2013 AACR.

Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers.

There is a vital need for improved therapeutic strategies that are effective in both primary and metastatic triple-negative breast cancer (TNBC). Current treatment options for TNBC patients are restricted to chemotherapy; however tyrosine kinases are promising druggable targets due to their high expression in multiple TNBC subtypes. Since coexpression of receptor tyrosine kinases (RTKs) can promote signaling crosstalk and cell survival in the presence of kinase inhibitors, it is likely that multiple RTKs will need to be inhibited to enhance therapeutic benefit and prevent resistance. The MET and EGFR receptors are actionable targets due to their high expression in TNBC; however crosstalk between MET and EGFR has been implicated in therapeutic resistance to single agent use of MET or EGFR inhibitors in several cancer types. Therefore it is likely that dual inhibition of MET and EGFR is required to prevent crosstalk signaling and acquired resistance. In this study, we evaluated the heterogeneity of MET and EGFR expression and activation in primary and metastatic TNBC tumorgrafts and determined the efficacy of MET (MGCD265 or crizotinib) and/or EGFR (erlotinib) inhibition against TNBC progression. Here we demonstrate that combined MET and EGFR inhibition with either MGCD265 and erlotinib treatment or crizotinib and erlotinib treatment were highly effective at abrogating tumor growth and significantly decreased the variability in treatment response compared to monotherapy. These results advance our understanding of the RTK signaling architecture in TNBC and demonstrate that combined MET and EGFR inhibition may be a promising therapeutic strategy for TNBC patients.

Phase II Trial to Evaluate Gemcitabine and Etoposide for Locally Advanced or Metastatic Pancreatic Cancer

Prior studies suggest that tumor cell lines harboring RAS mutations display remarkable sensitivity to gemcitabine and etoposide. In a phase II clinical trial of patients with locally advanced or metastatic pancreatic cancer, we evaluated the response rate to a combination of these drugs. Forty chemo-naïve patients with nonresectable and histologically confirmed pancreatic cancer were accrued. Patients received gemcitabine 1,000 mg/m2 (days 1 and 8) and etoposide 80 mg/m2 (days 8, 9, and 10; 21-day cycle). The primary end point was radiological response rate. Secondary objectives were determination of overall survival, response duration (time to progression), quality of life, toxicity, and CA 19-9 biomarker response. In 35 evaluable patients, 10 exhibited a radiological partial response and 12 had stable disease in response to treatment. Twenty patients exhibited a >20% decrease in CA 19-9 biomarker levels. Median overall survival was 6.7 months for all patients (40) and 7.2 months for evaluable patients (35). Notably, four patients survived for longer than 1 year, with two patients surviving for more than 2 years. Median time to progression for evaluable patients was 3.1 months. The median overall survival for locally advanced patients was 8.8 months and 6.75 months for metastatic patients. One-year survival was 10% for all patients and 11.4% for evaluable patients. Quality of life improved in 12 patients and remained stable in 3 of the evaluable patients. The primary dose-limiting toxicities were hematologic toxicity and fatigue. These results show that the gemcitabine and etoposide combination is generally well-tolerated and exhibits a response rate similar to other published studies. Mol Cancer Ther; 9(8); 2423–9. ©2010 AACR.

Outcomes of cytoreduction with hyperthermic intraperitoneal chemotherapy: our experience at a midwest community hospital

BACKGROUND Most cytoreduction with hyperthermic intraperitoneal chemotherapy procedures are performed at academic tertiary referral centers with numerous surgical oncology faculty. The objective of this study was to review the postoperative morbidity and mortality data of our institution, a large community hospital. METHODS This was a retrospective cohort study of patients who underwent cytoreduction with hyperthermic intraperitoneal chemotherapy at a single institution. Two surgical oncologists performed all the procedures between May 2005 and June 2011. RESULTS We retrospectively analyzed 57 patients. The most common pathology being treated was pseudomyxoma peritonei (34 of 57; 59.6%), followed by colorectal cancer (9 of 57; 15.8%). Other types of cancer included peritoneal mesothelioma and gastric adenocarcinoma. The average surgery time was 6.9 hours. Approximately 51% of patients suffered grade 3 or 4 morbidity and there were no perioperative mortalities. CONCLUSIONS Cytoreduction with hyperthermic intraperitoneal chemotherapy can be performed at our institution with comparable outcomes as academic referral centers.

Abstract 5041: The effect of YOCAS©® Yoga on prescription sleep medication and over-the-counter sleep medication usage in cancer survivors with impaired sleep quality

Background: Impaired sleep quality (ISQ) is highly prevalent among cancer survivors; 30-90% of cancer survivors report some form of ISQ following treatment. Cancer survivors with ISQ are often provided with sleep medications, which fall into two classes: prescription sleep medications (PSM) or over-the-counter sleep medications (OSM). The most common PSM are non-benzodiazepine hypnotics (NBH), benzodiazepines (BENZO), and tricyclic antidepressants (TCA). PSM have an uncertain efficacy, carry a risk of dependency, and may cause deleterious side effects. OSM (usually diphenhydramine and doxylamine) are believed to be safer, but the user can develop tolerance and often report a “groggy” feeling the next day. The aim of this secondary data analysis is to examine the effect of YOCAS©® Yoga for ISQ in cancer survivors on PSM and OSM usage. We also examined the baseline association between PSM, sleep quality, and side effects. Methods: We previously conducted a RCT among 410 cancer survivors suffering from moderate to severe ISQ between 2 and 24 months after treatment. The YOCAS©® program consisted of breathing exercises, 16 Gentle Hatha and Restorative yoga postures, and meditation. Participants attended two 75-minute sessions per week for four weeks. At baseline, participants listed all current prescription sleep medications while also completing questionnaires on sleep quality and side effects commonly experienced by cancer survivors. ANCOVA models were used to calculate the difference between groups while controlling for age, gender, race, and baseline values (where appropriate). Results: Previously published results showed YOCAS©® Yoga significantly improved ISQ compared to the control group. At baseline, 26% and 13% of participants reported using PSM and OSM, respectively. PSM users had significantly worse sleep quality (PSQI score: PSM=10.5 vs. No PSM=8.6; p Conclusion: PSM use was associated with ISQ along with side effects such as fatigue and memory problems at baseline. YOCAS©® yoga significantly reduced the use of NBH, which is currently the most used PSM. There was also a trend towards the reduction of OSM use with yoga. Clinicians may consider prescribing alternative therapies for ISQ such as YOCAS©® yoga, which improve ISQ and reduce the dependency on certain sleep medications. Citation Format: Luke J. Peppone, Michelle Janelsins, Jonathan Friedberg, Mohamed Tejani, Charles Kamen, Marie Flannery, Anita Peoples, James Atkins, Marianne Melnik, Karen Mustian. The effect of YOCAS©® Yoga on prescription sleep medication and over-the-counter sleep medication usage in cancer survivors with impaired sleep quality. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5041. doi:10.1158/1538-7445.AM2014-5041