Kellie S. Rath

HO-3867, a Safe STAT3 Inhibitor, Is Selectively Cytotoxic to Ovarian Cancer

STAT3 is well corroborated preclinically as a cancer therapeutic target, but tractable translational strategies for its blockade by small molecule inhibitors have remained elusive. In this study, we report the development of a novel class of bifunctional STAT3 inhibitors, based on conjugation of a diarylidenyl-piperidone (DAP) backbone to an N-hydroxypyrroline (-NOH) group, which exhibits minimal toxicity against normal cells and good oral bioavailability. Molecular modeling studies of this class suggested direct interaction with the STAT3 DNA binding domain. In particular, the DAP compound HO-3867 selectively inhibited STAT3 phosphorylation, transcription, and DNA binding without affecting the expression of other active STATs. HO-3867 exhibited minimal toxicity toward noncancerous cells and tissues but induced apoptosis in ovarian cancer cells. Pharmacologic analysis revealed greater bioabsorption and bioavailability of the active (cytotoxic) metabolites in cancer cells compared with normal cells. The selective cytotoxicity of HO-3867 seemed to be multifaceted, eliciting differential activation of the Akt pathway in normal versus cancer cells. RNAi attenuation experiments confirmed the requirement of STAT3 for HO-3867-mediated apoptosis in ovarian cancer cells. In vivo testing showed that HO-3867 could block xenograft tumor growth without toxic side effects. Furthermore, in primary human ovarian cancer cells isolated from patient ascites, HO-3867 inhibited cell migration/invasion and survival. Our results offer preclinical proof-of-concept for HO-3867 as a selective STAT3 inhibitor to treat ovarian cancer and other solid tumors where STAT3 is widely upregulated.

Burnout and associated factors among members of the Society of Gynecologic Oncology

OBJECTIVE Burnout is specific to the work domain and in physicians is indicative of emotional exhaustion, depersonalization in relationships with coworkers and detachment from patients, and a sense of inadequacy or low personal accomplishment. The purpose of this study was to determine the burnout rate among gynecologic oncologists and evaluate other personal, professional, and psychosocial factors associated with this condition. STUDY DESIGN This study used a cross-sectional design. Current members of the Society of Gynecologic Oncology were sent an anonymous email survey including 76 items measuring burnout, psychosocial distress, career satisfaction, and quality of life. RESULTS A total of 1086 members were invited, 436 (40.1%) responded, and 369 (84.6%) of those completed the survey. Of physicians, 30% scored high for emotional exhaustion, 10% high for depersonalization, and 11% low for personal accomplishment. Overall, 32% of physicians scored above clinical cutoffs indicating burnout. In all, 33% screened positive for depression, 13% endorsed a history of suicidal ideation, 15% screened positive for alcohol abuse, and 34% reported impaired quality of life. Nonetheless, 70% reported high levels of personal accomplishment, and results suggested most were satisfied with their careers, as 89% would enter medicine again and 61% would encourage their child to enter medicine. Respondents with high burnout scores were less likely to report they would become a physician again (P = .002) or encourage a child to enter medicine (P < .001), and more likely to screen positive for depression (P < .001), alcohol abuse (P = .006), history of suicidal ideation (P < .001), and impaired quality of life (P < .001). CONCLUSION Burnout is a significant problem associated with psychosocial distress and lower levels of career satisfaction in gynecologic oncologists. Burnout in obstetrics-gynecology and gynecologic oncology is of particular concern as young age and female gender are often identified as risk factors for this significant problem. Interventions targeted at improving quality of life, treatment of depression, or alcohol abuse may have an impact on burnout. However, significant barriers may exist as 44.5% of respondents in this study reported that they would be reluctant to seek medical care for depression, substance use, or other mental health issues due to concerns about their medical license.

Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic antitumor effects

Background: Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic herpes simplex virus-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for antitumor efficacy. Experimental Design: The synergistic interaction between oHSV and bortezomib was calculated using Chou–Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western blot assays were used to evaluate induction of estrogen receptor (ER) stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Antitumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan–Meier curves and two-sided log-rank test. Results: Combination treatment with bortezomib and oHSV (34.5ENVE), displayed strong synergistic interaction in ovarian cancer, head and neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK, and IRE1α (Western blot analysis) and the UPR (induction of hsp40, 70, and 90). Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (P < 0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced antitumor efficacy in multiple different tumor models in vivo. Conclusions: The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib-induced UPR and warrants future clinical testing in patients. Clin Cancer Res; 20(14); 3787–98. ©2014 AACR.

Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against metastatic ovarian cancer.

Purpose: Novel therapeutic regimens are needed to improve dismal outcomes associated with late-stage ovarian cancer. Oncolytic viruses are currently being tested in patients with ovarian cancer. Here, we tested the therapeutic efficacy of combining doxorubicin with 34.5ENVE, an oncolytic herpes simplex virus transcriptionally driven by a modified stem cell–specific nestin promoter, and encoding for antiangiogenic Vasculostatin-120 (VStat120) for use against progressive ovarian cancer. Experimental Design: Antitumor efficacy of 34.5ENVE was assessed in ovarian cancer cell lines, mouse ascites–derived tumor cells, and primary patient ascites–derived tumor cells by standard MTT assay. The ability of conditioned medium derived from 34.5ENVE-infected ovarian cancer cells to inhibit endothelial cell migration was measured by a Transwell chamber assay. Scope of cytotoxic interactions between 34.5ENVE and doxorubicin were evaluated using Chou–Talalay synergy analysis. Viral replication, herpes simplex virus receptor expression, and apoptosis were evaluated. Efficacy of oncolytic viral therapy in combination with doxorubicin was evaluated in vivo in the murine xenograft model of human ovarian cancer. Results: Treatment with 34.5ENVE reduced cell viability of ovarian cancer cell lines, and mouse ascites–derived and patient ascites–derived ovarian tumor cells. Conditioned media from tumor cells infected with 34.5ENVE reduced endothelial cell migration. When combined with doxorubicin, 34.5ENVE killed synergistically with a significant increase in caspase-3/7 activation, and an increase in sub-G1 population of cells. The combination of doxorubicin and 34.5ENVE significantly prolonged survival in nude mice bearing intraperitoneal ovarian cancer tumors. Conclusions: This study indicates significant antitumor efficacy of 34.5ENVE alone, and in combination with doxorubicin against disseminated peritoneal ovarian cancer. Clin Cancer Res; 20(24); 6479–94. ©2014 AACR.

Reducing readmissions after robotic surgical management of endometrial cancer:A potential for improved quality care

OBJECTIVE To describe readmission patterns after robotic surgery for endometrial cancer and identify risk factors for readmission within 90 days of discharge. METHODS Patients with endometrial cancer who underwent robotic surgical management at an academic institution from 2006 to 2010 were identified. Patient characteristics, intraoperative data, and postoperative complications were analyzed. Students t-test and Fishers exact test were used to compare patients readmitted within 90 days to those who were not. RESULTS Three hundred ninety-five patients were included. Thirty (7.6%) were readmitted within 90 days of surgical discharge. Length of stay greater than one day (40.0% vs. 23.0%, p=0.04) and postoperative complication (63.3% vs. 13.4%, p<0.01) were associated with readmission. The median interval to readmission was 9.5 days and median duration of subsequent hospitalization was 2.5 days. Fever (31.3%) and workup for vaginal drainage (25.0%) were the most common reasons for readmission. Only 2 of the 10 patients readmitted with fever had culture-proven infection, and no patients readmitted for vaginal drainage had a confirmed urinary tract injury. Of the 30 patients readmitted, 5 required a second operation - 3 for vaginal cuff dehiscence and 2 for port site hernia. CONCLUSIONS Robotic surgery for endometrial cancer was associated with a 7.6% readmission rate. The most common reasons for readmission, fever and evaluation for urinary tract injury, were frequently not associated with severe illness. This supports additional education to consider raising the threshold for readmission by using more widespread outpatient evaluation for the potential complications of robotic endometrial cancer surgery.

Safe and targeted anticancer therapy for ovarian cancer using a novel class of curcumin analogs

A diagnosis of advanced ovarian cancer is the beginning of a long and arduous journey for a patient. Worldwide, approximately half of the individuals undergoing therapy for advanced cancer will succumb to the disease, or consequences of treatment. Well-known and widely-used chemotherapeutic agents such as cisplatin, paclitaxel, 5-fluorouracil, and doxorubicin are toxic to both cancer and non-cancerous cells, and have debilitating side effects Therefore, development of new targeted anticancer therapies that can selectively kill cancer cells while sparing the surrounding healthy tissues is essential to develop more effective therapies. We have developed a new class of synthetic curcumin analogs, diarylidenyl-piperidones (DAPs), which have higher anticancer activity and enhanced bio-absorption than curcumin. The DAP backbone structure exhibits cytotoxic (anticancer) activity, whereas the N-hydroxypyrroline (-NOH) moiety found on some variants functions as a cellular- or tissue-specific modulator (antioxidant) of cytotoxicity. The anticancer activity of the DAPs has been evaluated using a number of ovarian cancer cell lines, and the safety has been evaluated in a number of non-cancerous cell lines. Both variations of the DAP compounds showed similar levels of cell death in ovarian cancer cells, however the compounds with the -NOH modification were less toxic to non-cancerous cells. The selective cytotoxicity of the DAP–NOH compounds suggests that they will be useful as safe and effective anticancer agents. This article reviews some of the key findings of our work with the DAP compounds, and compares this to some of the targeted therapies currently used in ovarian cancer therapy.

Outcomes following percutaneous upper gastrointestinal decompressive tube placement for malignant bowel obstruction in ovarian cancer.

OBJECTIVE The objective of this study was to evaluate peri-operative and survival outcomes of ovarian cancer patients undergoing percutaneous upper gastrointestinal decompression for malignant bowel obstruction (MBO). METHODS Retrospective chart review was used to identify patients with ovarian, peritoneal, or fallopian tube cancer who underwent palliative decompressive treatment for MBO from 1/2002 to 12/2010. Kaplan-Meier methods were used to estimate the median survival (MS) and multivariate analysis used to determine if any variables were associated with the hazard of death. RESULTS Fifty-three patients met inclusion criteria. Median length of diagnosis prior to intervention was 21 months. Fifteen (28.3%) patients experienced complications and 9 required revision. Forty-nine (92.5%) experienced relief of symptoms after placement, and 91% tolerated some form of oral intake. Following placement, 19 (36%) patients received additional chemotherapy and 21(41%) patients received total parental nutrition (TPN). Thirty-five patients were discharged home/outpatient facility, 16 to hospice care, and 2 died prior to discharge. MS for all patients was 46 days. Patients who received chemotherapy had a MS of 169 days compared to 33 days (p<0.001). We failed to find an association between survival and TPN or performance status. CONCLUSIONS Malignant bowel obstruction is a common complication of ovarian cancer. Management is palliative; risks and benefits of any therapy must be considered. Percutaneous decompressive therapy provides relief from associated symptoms, and allows patients to be discharged home. Median survival in this group is limited, and decisions regarding aggressive therapy should be individualized.

Recurrent ovarian cancer: Is there a role for re-treatment with bevacizumab after an initial complete response to a bevacizumab-containing regimen?

OBJECTIVE To compare the progression free survival (PFS) and overall survival (OS) in patients with epithelial ovarian cancer (EOC) who received Bev after Bev (BAB) vs. those who were not re-treated with Bev (NOTBev) after initially experiencing a complete response (CR) to a Bev-containing regimen (BCR). METHODS We performed a retrospective chart review of patients with EOC that received Bev in either the front-line or recurrent setting. Patients who received additional therapy after achieving a CR to BCR were analyzed. RESULTS 36 patients who had a CR to a BCR were included, 17 who received Bev at the time of their subsequent recurrence vs. 19 that did not. More patients in the NOTBev group received Bev as primary therapy (21% vs. 6%, p=0.2), but this was not statistically significant. Patients in the BAB group had significantly higher mean PFS compared to the NOTBev group (20 vs. 6 months, p=0.0019). On adjusting for covariates, there was a 78% improvement in their PFS (HR 0.22, p=0.0048). No difference in overall survival was noted between the groups (23 vs. 26 months, p=0.7244). CONCLUSIONS Re-treatment with Bev after a prior Bev response is associated with a significantly improved PFS. This is the first of such reports in this patient population. The 14-month improvement in PFS strongly supports the re-use of Bev in patients who demonstrate an initial response to Bev. This strategy should be formally tested in future clinical trials and further investigation should include evaluation of predictors of response to Bev therapy.

Stress and burnout among gynecologic oncologists: A Society of Gynecologic Oncology Evidence-based Review and Recommendations

Burnout in physicians is a significant problem in all fields of medicine. A 2008 survey of members of the American College of Surgeons (ACS) and a 2014 survey of members of the Society of Gynecologic Oncology (SGO) reported that physician burnout occurs in 32% to 40% of gynecologic oncologists and surgeons This article describes the risk factors responsible for burnout in gynecologic oncologists and other physicians and the consequences of burnout and explores potential solutions. Data from the oncology, trauma, and surgical literature have shown that physicians treating themost acutely ill patients have 40% or greater prevalence of burnout. At the individual level, burnout is indicative of emotional exhaustion and stress, depersonalization in relationships with coworkers, detachment from patients, a sense of inadequacy or low personal accomplishment, mental illness, substance abuse, and risk of suicide. In the SGO survey, 33% of respondents screened positive for depression, 11% took medication for depression, and 14% experienced panic attacks. The ACS survey corroborated these findings, reporting that 30% of surgeons screened positive for symptoms of depression. Substance abuse was identified in 15% of gynecologic oncologists; there was a positive screen for alcohol abuse and suicidal ideation. The SGO survey reported that only 9% of respondents had sought psychiatric care in the previous 12months, and 45%were reluctant to seek psychiatric care. Suicide is a significant problem among all physicians who experience burnout; suicide rates are higher among female physicians. In both the SGO survey and the ACS survey, 13% to 14% of respondents reported suicidal ideation. At the professional level, physician burnout impacts patient care as shown by suboptimal patient outcomes, increased medical errors, increased liability claims, and inappropriate prescriptions. Because few studies have specifically assessed burnout in gynecologic oncologists, much of what is understood about burnout has been extrapolated from a variety of other physician specialties. Risk factors for burnout: Job stress is one of the most important factors associated with physician burnout. Gynecologic oncologists with a low perception of internal locus of control and increased anxiety with end-of-life care have greater work-related stress. Loss of a sense ofmeaning fromwork has been shown to increase the risk of physician burnout. Changing interests and career drift can develop over time. Gynecologic oncologists who devote most of their time and effort to patient care and surgery may find that they derive more job satisfaction and meaning in research and be unable to do so. The difficulty balancing career with family/personal life is a key factor contributing to burnout. In the AGS survey, worklife balance issues predicted burnout equally in both sexes, but the effect was more pronounced among female physicians. Modern home computer technology has a major affect on work-life balance in that physicians have 24-hour access to patient records, shared communication with colleagues, and on-demand educational resources. Risk factors for burnout in the AGS survey were having younger children between the ages of 5 and 21 years, income based on patient care billing, and working at least 60 hours per week. The SGO survey reported that independent risk factors associated with burnout were low mental quality of life, depression, being stressed and overwhelmed, suicidal ideation, alcohol abuse, and reluctance to seek care. The findings of a large study among US physicians assessing work-home conflict in dual-career relationships reported that female physicians were more likely to report signs or symptoms of burnout than male physicians. Copyright

Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by HO-3867, a novel STAT3 inhibitor

OBJECTIVE Constitutive activation of STAT3 is a hallmark of various human cancers, however an increased pSTAT3 expression in high grade human endometrial cancer has not been reported. In the present study, we examine the expression of STAT family of proteins in endometrial cancer cell lines and the efficacy of HO-3867, a novel STAT3 inhibitor designed in our lab. METHODS Expression of STAT family proteins was evaluated via Western blot. The cell viability, post-treatment with HO-3867, was assessed using MTT, cell-cycle profile and Annexin assay. In vivo efficacy of HO-3867 was evaluated using xenograft mice. RESULTS Expression of activated STATs was inconsistent among the cell lines and 18 human endometrial cancer specimens tested. While pSTAT3 Tyr705 was not expressed in any of the cell lines, pSTAT3 Ser727 was highly expressed in endometrial cancer cell lines and tumor specimens. HO-3867 decreased the expression of pSTAT3 Ser727 while total STAT3 remained constant; cell viability decreased by 50-80% and induced G2/M arrest in 55% of Ishikawa cells at the G2/M cell cycle checkpoint. There was an increase in p53, a decrease in Bcl2 and Bcl-xL, and cleavage of caspase-3, caspase-7 and PARP. HO-3867 mediated a dosage-dependent inhibition of the growth of xenografted endometrial tumors. CONCLUSIONS HO-3867 treatment decreases the high levels of pSTAT3 Ser727 in endometrial cancer cells by inducing cell cycle arrest and apoptosis. This suggests a specific role of serine-phosphorylated STAT3, independent of tyrosine phosphorylation in the oncogenesis of endometrial cancer. HO-3867 could potentially serve as an adjunctive targeted therapy.