Molecular targets in serous gynecologic cancers

Abstract

In this thesis we describe a series of studies assessing the effectiveness of targeted therapeutics that inhibit Notch signaling or the HER2 receptor in serous gynecologic cancers. In the first part of the thesis, we have confirmed previous data by showing expression of Notch1 and Notch3 in ovarian cancer. Inhibition of the Notch pathway with a gamma-secretase inhibitor (GSI) reduced cell proliferation of ovarian cancer cell lines in vitro. We subsequently utilized patient derived serous ovarian cancer xenografts to study the efficacy of this GSI in vivo and demonstrated single agent anti-tumor activity in half of the analyzed tumors. In addition, a synergistic effect of treatment with GSI in combination with paclitaxel on xenograft growth was found in all analyzed tumors known to be clinically platinum resistant. These findings support previous data showing involvement of Notch signaling in chemoresistance. In addition to our research on Notch inhibition in ovarian cancer, this thesis comprises the first study to date of Notch signaling and the therapeutic targeting of this pathway in uterine serous carcinoma (USC). Expression of Notch1 was shown in the majority of analyzed USCs and in vitro treatment with GSI decreased proliferation of USC cell lines. Furthermore, GSI monotherapy in vivo reduced tumor growth in a subset of cell line derived and patient derived USC xenograft models. Moreover, GSI treatment augmented the anti-tumor activity of paclitaxel and carboplatin in half of the primary human USC xenograft cohorts.

In the second part of this thesis, we have assessed the efficacy of HER2 inhibition in USC using the monoclonal anti-HER2 antibody trastuzumab and the tyrosine kinase inhibitor lapatinib. In our cohort of USC specimens, a 24% rate of HER2 gene amplification and a 55% HER2 over-expression rate were found. None of the analyzed cell lines or primary human USCs responded to in vitro or in vivo trastuzumab therapy. In contrast, lapatinib as single agent reduced proliferation of all USC cell lines in vitro and in vivo inhibited tumor growth only in the HER2 amplified xenografts. The most robust anti-tumor activity was observed in HER2 amplified xenografts when lapatinib was combined with trastuzumab. No in vivo efficacy of anti-HER2 therapy was found in non-HER2 amplified xenografts, suggesting HER2 gene amplification to be a biomarker for response to HER2 inhibition in USC. Next, we investigated p95HER2 expression in USC and high grade endometrioid endometrial cancer. Expression of this truncated variant of the HER2 receptor has been associated with trastuzumab resistance in breast cancer. We observed a lower degree of total HER2 expression with a proportionally higher p95HER2 expression level in USC and high grade endometrioid tumors, as compared to co-analyzed breast carcinomas. The differential p95HER2 expression levels between breast cancer and USC provide rationale for the trastuzumab resistance observed in USC.

In conclusion, the reported preclinical effectiveness of inhibition of Notch and HER2 in ovarian and uterine serous carcinomas suggests that these targeted therapies are promising strategies in serous gynecologic tumors, warranting further investigation in a clinical setting.