Brent J. Tierney

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.

HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells

BRCA1 plays an important role in DNA damage and repair, homologous recombination, cell-cycle regulation and apoptosis. BRCA-mutated ovarian cancer often presents at an advanced stage, however, tend to have better response to platinum-based chemotherapy as compared with sporadic cases of epithelial ovarian cancer (EOC). In spite of this, most patients will develop a recurrence and eventually succumb to the disease. Preclinical studies are currently investigating natural compounds and their analogs for tumor-directed targets in ovarian cancer. The aim of this study is to investigate whether the STAT3 inhibitor HO-3867, a novel curcumin analog, has a therapeutic effect on BRCA1-mutated ovarian cancer. Our novel agent, HO-3867 and a commercial STAT3 inhibitor, STATTIC, significantly inhibited BRCA-mutated ovarian cancer cells in vitro in a dose- and time-dependent manner. BRCA-mutated ovarian cancer cells treated with HO-3867 exhibited a significant degree of apoptosis with elevated levels of cleaved caspase-3, caspase-7 and PARP. HO-3867 treatment induced more reactive oxygen species (ROS) in BRCA-mutated cells compared with wild-type cells, however, there was no increased ROS when benign ovarian surface epithelial cells were treated with HO-3867. BRCA1-mutated cancer cells had higher expression of Tyrosine-phosphorylated STAT3 (pTyr705) as compared with other STAT proteins. Furthermore, treatment of these cells with HO-3867 resulted in decreased expression of pTyr705 and its downstream targets cyclin D1, Bcl-2 and survivin. In addition, overexpression of STAT3 cDNA provided resistance to HO-3867-induced apoptosis. Our results show that HO-3867, a potent STAT3 inhibitor, may have a role as a biologically targeted agent for BRCA1-mutated cancers either as an adjunct to cytotoxic chemotherapy or as a single agent.

Complications after double-barreled wet colostomy compared to separate urinary and fecal diversion during pelvic exenteration: Time to change back?

OBJECTIVE To assess complications associated with double-barreled wet colostomy (DBWC) in the first six months after pelvic exenteration as compared to separate urinary and fecal diversion (SUD). METHODS A single institution retrospective chart review was conducted of all patients who underwent a pelvic exenteration between 2000 and 2011. Patients were included if the procedure involved at least a urinary diversion and a perineal phase. Patient demographics and complications in the first 6months after surgery were recorded. RESULTS Thirty-three patients met inclusion criteria (12 DBWC and 21 SUD). The majority of patients had recurrent cervical cancer (58%) followed by vaginal, vulva, and endometrial cancer. All patients had previously received radiation. 10/12 patients with a DBWC and 67% of SUD had pelvic reconstruction. Median length of stay (LOS) was shorter for DBWC (14.5 vs. 20days, p=.01). Median operating times were shorter for DBWC (610 vs. 702minutes, p=.04). No urinary conduit or anastomotic bowel leaks occurred in the DBWC group compared to 5 (24%) and 2 (9.5%), respectively, in the SUD group (p=.06 for any leak). 58% of the DBWC and 62% of the SUD group required re-operation, and there were no 30-day peri-operative deaths. CONCLUSIONS DBWC can be performed safely at the time of pelvic exenteration. We found reduced operating times, shorter LOS, and a trend toward fewer urinary conduit and/or bowel anastomotic leaks in DBWC exenteration patients. DBWC may be favorable over more technically challenging SUD in this heavily radiated population that generally has a limited overall survival.

Does intra-operative radiation at the time of pelvic exenteration improve survival for patients with recurrent, previously irradiated cervical, vaginal, or vulvar cancer?

OBJECTIVE To determine whether intra-operative radiation therapy (IORT) at the time of pelvic exenteration (PE) or laterally extended endopelvic resection (LEER) improves progression-free survival (PFS) in patients with recurrent, previously irradiated gynecologic cancers. METHODS We conducted a single institution retrospective review of patients who had undergone a complete PE for locally recurrent gynecologic cancer. Demographic and clinicopathologic data were collected. RESULTS 32 patients were identified (2000-2012); 21 (66%) cervical cancer, 8 (25%) vaginal, and 3 (9%) vulvar cancer. All patients were previously irradiated. Twenty-one (66%) received IORT. Mean age was 51. Eight patients had a LEER, all with IORT. Median PFS and OS, respectively, for those with PE alone was 33 and 41 vs. 10 and 10 months for PE+IORT compared to 9 and 17 months for LEER+IORT (P=.04). Increasing tumor size negatively impacted PFS (hazard ratio 1.3; 95%CI 1.12-1.52). Margin status was not associated with survival. No patients undergoing LEER+IORT recurred only locally whereas 62% recurred with a distant component (+/- local). Patients with PE alone had mainly local (36%) and few (9%) distant recurrences compared to 31% local and 38% distant (+/- local) recurrences for those with PE+IORT. CONCLUSIONS We failed to demonstrate that IORT changes survival and recurrence outcomes. However, patients with clinical indications for IORT at the time of PE have worse prognosis compared to those who do not require IORT. If the need for IORT is anticipated, the surgeon may consider performing a LEER to decrease local recurrence if cure is the goal or consider palliative treatment options.

Is selective lymphadenectomy more cost-effective than routine lymphadenectomy in patients with endometrial cancer?

OBJECTIVE The objective of this study is to determine the cost-effectiveness of two strategies in women undergoing surgery for newly diagnosed endometrial cancer. METHODS A decision analysis model compared two surgical strategies: 1) routine lymphadenectomy independent of intraoperative risk factors or 2) selective lymphadenectomy for women with high or intermediate risk tumors based on intraoperative assessment including tumor grade, depth of invasion, and tumor size. Published data were used to estimate the outcomes of stage, adjuvant therapy, and recurrence. Costs of surgery, radiation, and chemotherapy were estimated using Medicare Current Procedural Technology codes and Physician Fee Schedule. Cost-effectiveness ratios were estimated for each strategy. Sensitivity analyses were performed including an estimate for lymphedema for patients that underwent a lymphadenectomy. RESULTS For 40,000 women diagnosed annually with endometrial cancer in the United States, the annual cost of selective lymphadenectomy is

Is the progression free survival advantage of concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin in patients with advanced cervical cancer worth the additional cost? A cost-effectiveness analysis

1.14 billion compared to

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

1.02 billion for routine lymphadenectomy. The selective lymphadenectomy strategy cost an additional

Abstract 2802: Selective inhibition of signal transducers and activators of transcription 3 overexpressing endometrial cancer cells, using HO-3867, a novel STAT3 inhibitor

123.3 million. Five-year progression-free survival was 85.9% in the routine strategy compared to 79.3% in the selective strategy. Treatment cost

Ureteroarterial fistula following retrograde ureteral stenting in a patient with a double-barreled wet colostomy for cervical cancer

6349 more per survivor in the selective strategy compared to routine strategy (

Abstract POSTER-THER-1413: Targeting constitutively-activated STAT3 in hypoxic ovarian cancer

36,078 vs.