Abstract P6-13-17: The combination of eribulin and everolimus results in enhanced suppression of tumors in mouse models of triple negative breast cancer
Authors: Marcinkowski E , Luu T , Yuan Y , Mortimer J , Leong L , Portnow J , Xing Q , Wen W , Yim J 
Published: May 2016

INTRODUCTION. Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with poor overall and relapse free survival. TNBC does not have targeted or matched therapies. Patients have worse outcomes after chemotherapy than with other subtypes of breast cancer. TNBC accounts for 12-17% of all breast cancers, leaving an unmet need for targeted therapy. Efforts to profile these tumors have revealed several potential targets.

The PI3K/AKT/mTOR pathway is a signal transduction pathway that links growth related hormone receptor interaction to downstream targets such as AKT and mammalian target of rapamycin (mTOR). This pathway targets affect cell proliferation, survival, and apoptosis. Patients with TNBC have high levels of AKT expression and activation of this pathway.

Microtubule-targeting agents have been used in TNBC. Eribulin mesylate is a microtubule-targeting agent with benefits in treating taxane and anthracycline refractory breast cancer via a microtubule targeting anti-mitotic mechanism. It has been approved for the treatment of TNBC in heavily pretreated patients.

Despite targeted therapy, breast cancer cells can grow resistant. Targeting multiple cancer growth pathways has been used in patients that progress on therapy or fail to respond. We hypothesized that targeting both mitotic blockade and PI3K/AKT/mTOR pathway may provide enhanced suppression of TNBC growth in both syngeneic and xenogeneic mouse models.

MATERIALS AND METHODS. MDA-MB-468 is a human TNBC cell line. 4T1 is a highly metastatic mouse TNBC cell line derived from a spontaneously arising Balb/c mammary tumor. 4T1 and MDA-MB-468 tumor cells were injected into the mammary fat pad of female Balb/c and NOD/SCID/IL2Rgamma null (NSG) mice (with matrigel) respectively. After tumors were formed Balb/c mice were treated three times per week with vehicle, eribulin (0.75 mg/kg i.v.), RAD001 (5 mg/kg via oral gavage) or a combination of both. NSG mice were treated three times per week with vehicle, eribulin (0.5 mg/kg i.v.), RAD001 (5 mg/kg by oral gavage), or a combination of both. Tumor volumes and body weights were measured. Student t-test was used to compare the means of two groups and determine the p value (p&lt;0.05 is significant). N=3-8 per group.

Table I. 4T1 mouse breast cancer modelTreatmentTumor Volume (mm3)+/-SEMVehicle511.6+/-56.82Eribulin445.6+/-92.17Everolimus324.9+/-24.55Combination171.4+/-16.07 p valueCombination vs. Vehicle0.0001Combination vs. Eribulin0.01Combination vs. Everolimus0.001

Table II. MDA-MB-468 human breast cancer cells in immune deficient mice.TreatmentTumor Volume (mm3)+/-SEMVehicle966.8+/-69.2Eribulin67.81+/-11.79Everolimus830.6+/-156.3Combination31.37+/-3.37 p valueCombination vs. Eribulin0.041Combination vs. Everolimus0.0076

RESULTS. In the 4T1 syngeneic breast cancer mouse model, the combination of Eribulin and Everolimus resulted in marked suppression of tumor growth which was statistically significant versus vehicle treatment alone, or Eribulin or Everolimus alone (Table I). In the MDA-MB-468 model, the combination of Eribulin and Everolimus demonstrated marked suppression of tumor growth which was statistically significant compared to either agent alone (Table II).

Citation Format: Marcinkowski E, Luu T, Yuan Y, Mortimer J, Leong L, Portnow J, Xing Q, Wen W, Yim J. The combination of eribulin and everolimus results in enhanced suppression of tumors in mouse models of triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-17.