Ernest S. Han

PREDICTIVE AND PROGNOSTIC ANGIOGENIC MARKERS IN A GYNECOLOGIC ONCOLOGY GROUP PHASE II TRIAL OF BEVACIZUMAB IN RECURRENT AND PERSISTENT OVARIAN OR PERITONEAL CANCER

OBJECTIVE Potential predictive/prognostic angiogenic markers were prospectively examined in a phase II trial of bevacizumab in epithelial ovarian cancer (EOC)/primary peritoneal cancer (PPC). METHODS Recurrent/persistent EOC/PPC patients were treated with bevacizumab (15 mg/kg IV q21days) until disease progression. Validated-immunohistochemistry (IHC) assays were performed on pre-cycle 1/4 tumor biopsies for CD31-microvessel density (MVD), VEGF-histoscore (HS), p53-HS, and TSP1 image analysis score (IA). Pre-cycle 1/4 serum and plasma VEGF were quantified using a validated-ELISA. RESULTS CD31-MVD and serum VEGF, evaluated pre-cycle 1 in 41/61 and 51/61 eligible patients, respectively, did not appear to be correlated. High CD31-MVD, categorized at the median, appeared to be associated with tumor response, a 13-month shorter median survival, and an increased risk of death (unadjusted hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.067-4.467). In addition, each standard deviation (SD) increase in CD31-MVD appeared to be associated with worse survival in unadjusted and adjusted analyses. IHC and plasma biomarkers did not change with bevacizumab treatment except for serum VEGF, which appeared to decrease during bevacizumab treatment. This decrease was not associated with response. High pre-cycle 1 serum VEGF, categorized at the median, was associated with 22-month shorter median survival and an increased risk of death (unadjusted HR = 2.7, 95% CI = 1.369-5.191). Categorized p53 appeared to be associated with unadjusted survival and each SD increase in TSP1-IA appeared to be associated with a decreased risk of progression in unadjusted and adjusted analyses. CONCLUSIONS Despite the limitations in sample size and exploratory nature of the study, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent EOC/PPC, and are being prospectively evaluated in the GOG phase III trial of carboplatin, paclitaxel and bevacizumab/placebo in previously untreated EOC/PPC.

Practical considerations in ovarian cancer chemotherapy

Epithelial ovarian cancer remains the most lethal gynecologic malignancy despite advances in treatment. The standard management generally involves a combination of surgical tumor debulking and chemotherapy. Over the decades, chemotherapy for ovarian cancer has evolved and currently involves a combination of intravenous platinum and taxane chemotherapy. Over the past decade, three randomized phase III trials have been reported, and all have demonstrated a significant survival advantage for intraperitoneal compared with intravenous chemotherapy. However, there are potential barriers and controversies related to the administration of intraperitoneal chemotherapy in ovarian cancer patients. In this review, we discuss the evolution and current management considerations of chemotherapy for the treatment of epithelial ovarian cancer.

Current Status on Biologic Therapies in the Treatment of Epithelial Ovarian Cancer

Treatment of epithelial ovarian cancer generally involves surgical staging followed by chemotherapy with a combination of a platinum and a taxane-containing agent. However, a majority of patients recur and ultimately succumb to their cancer. Novel therapies that target specific pathways involved in ovarian tumorigenesis are rapidly emerging. In ovarian cancer, targeted therapies have focused on both the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways. Single-agent bevacizumab, a VEGF inhibitor, demonstrated significant clinical activity in multiple phase II studies. Various combinations of cytotoxic and biologic agents with bevacizumab as well as newer anti-angiogenesis agents are being tested. In contrast, EGFR inhibitors have not shared the same clinical activity in epithelial ovarian cancers as compared to the VEGF inhibitors. Translational studies are needed to help design rational combinations of targeted agents and to help predict response to therapy.

Role of Robotic Surgery in Endometrial Cancer

Opinion statementUterine cancer is the most common gynecologic cancer in women in the United States with an estimated number of 40,100 women diagnosed in 2008, the great majority of which belongs to endometrial classification. The traditional approach to treatment of endometrial cancer has been primarily surgery via an open, laparotomy incision. Minimally invasive approaches with smaller incisions, i.e., laparoscopy for the management of endometrial cancer was initially reported in 1992; however, its adoption has been slow due to the prolonged learning curve needed to become proficient in such a technique. Robotic-assisted surgery, a further advancement of traditional laparoscopy, using computer-based controls has been developed enabling the performance of complex procedures that otherwise had been too difficult to accomplish in a minimally invasive fashion. Robotic-assisted laparoscopic radical prostatectomy is one such example that has gained rapid acceptance in recent years. Although the use of robotic-assisted laparoscopy for endometrial cancer is still in its early phase, this approach is anticipated to become similarly, a common approach to the management of endometrial cancer in the future.

Intraperitoneal Administration of Neural Stem Cell–Nanoparticle Conjugates Targets Chemotherapy to Ovarian Tumors

Ovarian cancer is particularly aggressive once it has metastasized to the abdominal cavity (stage III). Intraperitoneal (IP) as compared to intravenous (IV) administration of chemotherapy improves survival for stage III ovarian cancer, demonstrating that concentrating chemotherapy at tumor sites has therapeutic benefit; unfortunately, IP therapy also increases toxic side effects, thus preventing its completion in many patients. The ability to target chemotherapy selectively to ovarian tumors while sparing normal tissue would improve efficacy and decrease toxicities. We have previously shown that tumor-tropic neural stem cells (NSCs) dramatically improve the intratumoral distribution of nanoparticles (NPs) when given intracerebrally near an orthotopic brain tumor or into a flank xenograft tumor. Here, we show that NPs either conjugated to the surface of NSCs or loaded within the cells are selectively delivered to and distributed within ovarian tumors in the abdominal cavity following IP injection, with no evidence of localization to normal tissue. IP administration is significantly more effective than IV administration, and NPs carried by NSCs show substantially deeper penetration into tumors than free NPs. The NSCs and NPs target and localize to ovarian tumors within 1 h of administration. Pt-loaded silica NPs (SiNP[Pt]) were developed that can be transported in NSCs, and it was found that the NSC delivery of SiNP[Pt] (NSC-SiNP[Pt]) results in higher levels of Pt in tumors as compared to free drug or SiNP[Pt]. To the best of our knowledge, this work represents the first demonstration that cells given IP can target the delivery of drug-loaded NPs.

Effect of eribulin on cell growth and PI3K pathway activity with and without RAD001 in triple-negative and HER2-expressing breast cancer.

173 Background: Patients with triple-negative breast cancer have high levels of Akt expression and activation of the PI3K-mTOR pathway. Eribulin is a microtubule-targeting agent with benefits in treating refractory triple negative disease. Our objective was to evaluate its efficacy in inhibiting PI3K pathway activity and cell growth both alone and in combination with the mTOR inhibitor RAD001. METHODS MDA468, BT549 and SKBR3 breast cancer cell lines were used for this study. MTT assays were used to assess growth inhibition after 72 hour treatment with eribulin alone and in combination with RAD001. Combination indices (CI) generated by Chou-Talalay plots were used to quantify synergy. Western blots were used to evaluate the expression of phosphorylated Akt-Ser473 (pAkt) and S6K1 after 24 hours of treatment with both agents. RESULTS Both MDA468 and SKBR3 cells treated with eribulin in varying concentrations showed inhibition of pAkt expression. Standard dilutions of eribulin in combination with log dilutions of RAD001 resulted in marked synergistic growth inhibition (CI<<1) in both MDA468 and BT549 cells. Western blot analysis for MDA468 cells treated with the combination erubulin and RAD001 showed a dose related suppression of pAkt along with complete inhibition of pS6K1, while RAD001 alone increased pAkt. CONCLUSIONS Our study shows dose related inhibition of Akt activation as well as inhibition of cell growth in triple negative breast cancer and HER2 cell lines treated with eribulin alone or combined with RAD001. We also show reversal of the pAkt feedback response seen with mTOR inactivation, and a significant synergistic growth inhibition with combination treatment. These findings point to a potential role for eribulin and RAD001 in the treatment of refractory triple-negative breast cancer. [Table: see text].

Pterostilbene, a natural phenolic compound, synergizes the antineoplastic effects of megestrol acetate in endometrial cancer

Endometrial cancer is the most common gynecologic cancer in the United States and its incidence and mortality has been rising over the past decade. Few treatment options are available for patients with advanced and recurring endometrial cancers. Novel therapies, which are frequently toxic, are difficult to establish in this patient population which tends to be older and plagued by comorbidities such as diabetes mellitus and hypertension. Therefore, novel, non-toxic therapies are urgently needed. Megestrol acetate is a frequently used drug in endometrial cancer patients. However, its response rate is only 20–30%. To enhance the activity of megestrol acetate in endometrial cancer patients, we explored the potential of combining natural supplements with megestrol acetate and found that the addition of the natural phenolic compound, pterostilbene, to megestrol acetate resulted in a synergistic inhibition of cancer cell growth in vitro and an enhanced reduction of tumor growth in a xenograft mouse model. In addition, dual treatment led to attenuation of signaling pathways, as well as cell cycle and survival pathways. Our results demonstrated for the first time that the anti-tumor activity of megestrol acetate can be enhanced by combining with pterostilbene, providing an insight into the potential application of pterostilbene and megestrol acetate combination for the treatment of endometrial cancer.

Association of Fluid Administration With Morbidity in Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy

Importance Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal cancers can be associated with significant complications. Randomized trials have demonstrated increased morbidity with liberal fluid regimens in abdominal surgery. Objective To investigate the association of intraoperative fluid administration and morbidity in patients undergoing CRS/HIPEC. Design, Setting, and Participants A retrospective analysis of information from a prospectively collected institutional database was conducted at a National Cancer Institute–designated comprehensive cancer center. A total of 133 patients from April 15, 2009, to June 23, 2016, with primary or secondary peritoneal cancers were included. Exposures Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Main Outcomes and Measures Morbidity associated with intraoperative fluid management calculated by the comprehensive complication index, which uses a formula combining all perioperative complications and their severities into a continuous variable from 0 to 100 in each patient. Results Of the 133 patients identified, 38% and 37% had diagnoses of metastatic appendiceal and colorectal cancers, respectively. Mean age was 54 (interquartile range [IQR], 47-64) years, and mean peritoneal cancer index was 13 (IQR, 7-18). Mitomycin and platinum-based chemotherapeutic agents were used in 96 (72.2%) and 37 (27.8%) of the patients, respectively. Mean intraoperative fluid (IOF) rate was 15.7 (IQR, 11.3-18.7) mL/kg/h. Mean comprehensive complication index (CCI) was 26.0 (IQR, 8.7-36.2). On multivariate analysis, age (coefficient, 0.32; 95% CI, 0.01-0.64; P = .04), IOF rate (coefficient, 0.97; 95% CI, 0.19-1.75; P = .02), and estimated blood loss (coefficient, 0.02; 95% CI, 0.01-0.03; P = .002) were independent predictors of increased CCI. In particular, patients who received greater than the mean IOF rate experienced a 43% increase in the CCI compared with patients who received less than the mean IOF rate (31.5 vs 22.0; P = .02). Conclusions and Relevance Intraoperative fluid administration is associated with a significant increase in perioperative morbidity in patients undergoing CRS/HIPEC. Fluid administration protocols that include standardized restrictive fluid rates can potentially help to mitigate morbidity in patients undergoing CRS/HIPEC.

Abstract P3-03-15: Synergistic suppression of triple negative breast cancer with the combination of PI3K inhibitor (alpelisib, BYL719) and CDK inhibitor (ribociclib, LEE011)

INTRODUCTION. Triple negative breast cancer (TNBC) is an aggressive form of BC that lacks effective targeted therapy. It is a biologically heterogeneous disease with several molecular subtypes: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal-stem-like (MSL), immune-modulatory (IM) and unclassified (UNC). The PI3K/AKT/mTOR pathway affects cell proliferation, survival, and apoptosis through growth receptor interaction with downstream targets such as AKT and mTOR. TNBC frequently has activation of this pathway by mutation and other means across several subtypes. Recently the PI3K inhibitor alpelisib (BYL719) has been found to have efficacy in a combination study in ER positive metastatic BC (MBC) with a Phase 3 trial in progress. Ribociclib (LEE011) is a CDK inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 that recently met its primary endpoint in a phase 3 trial in a combination study in hormone receptor positive BC. As with all BC, TNBC has intact or mutant RB which affects susceptibility to CDK inhibitor. We hypothesize that targeting both PI3K with alpelisib and CDK with ribociclib may provide enhanced suppression of TNBC. MATERIALS AND METHODS. HCC38 and MDA468 are TNBC subtype BL1; MDA468 is RB1 and PTEN mutant. HCC1187 is IM. BT549 is M, mutant RB1 and PTEN. Hs578T, MDA157, and MDA231 are MSL. Cells were treated with alpelisib and ribociclib alone with 2-fold increase in concentrations, or the combination, for 72h and assessed by MTT assay. Western blot was performed using probes for pAkt (T308 and S473), Akt, pS6K1, S6K1, pS6, S6, and β-actin. RESULTS. Synergy in growth inhibition was seen combining alpelisib and ribociclib as reflected by combination indices Conclusion. Our study demonstrates that alpelisib plus ribociclib can synergistically enhance suppression of BC across multiple subtypes of TNBC. Cancer cells within the same subtype may not demonstrate a synergistic response, depending on RB status. Nevertheless, if RB mutant cells are susceptible to ribociclib then synergy can be seen even in these cancer cells. Antagonism can be seen independent of RB status in the same subtype. These findings point to a potential role for combination therapy with alpelisib and ribociclib in the treatment of TNBC. Citation Format: Yuan Y, Mortimer J, Xing Q, Yan J, Wen W, Han E, Yim JH. Synergistic suppression of triple negative breast cancer with the combination of PI3K inhibitor (alpelisib, BYL719) and CDK inhibitor (ribociclib, LEE011) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-15.

Abstract 2183: Baicalein and meformin decrease small cell lung cancer growth by inhibiting the mTOR pathway in itro

Background: Metformin use has been associated with decreased lung cancer risk in several observational studies and is currently in clinical trial in conjunction with standard chemotherapeutics. One possible antitumor mechanism is the negative regulation of the mTOR pathway. We previously reported that the natural product Baicalein has antitumor effects through targeting mTOR pathway. We hypothesized that Baicalein to have antitumor effects in small cell lung cancer. Methods: H1417 small cell lung cancer cells were cultured and treated with increasing doses of Baicalein or Metformin. The cells were harvested at 24 hours and subjected to Western blotting staining for the downstream products of the mTOR pathway. Cell proliferation was determined by MTT assay at 24, 48, and 72 hours. MTT conversion to formazan dye correlates with the number of living cells. Results: We found a dose dependent decrease in the downstream mTOR1 targets pS6K1 and pS6 using both Baicalein and Metformin. There was also an increase in the expression of the mTOR inhibitors DDIT4 and IRF-1. Using the MTT assay, we were able to demonstrate a marked dose dependent decrease in cell proliferation that was sustained over 72 hours from treatment. Interestingly, Baicalein has a markedly higher potency working at micromolar doses verses Metformin which required millimolar doses. Conclusions: Both Baicalein and Metformin effectively decrease cell proliferation in small cell lung cancer cells in vitro. We have shown these drugs to target the mTOR pathway. Cell proliferation is inhibited at a markedly smaller dose by Baicalein compared with Metformin. Baicalein may be useful in cancer chemotherapy and chemoprevention. Citation Format: Emily F. Marcinkowski, Dan Raz, Bing Shen, Quanhua Xing, Jin Yan, Wei Wen, Ernest Han, John Yim. Baicalein and meformin decrease small cell lung cancer growth by inhibiting the mTOR pathway in itro. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2183.