Molecular Pathways: Targeting Steroid Receptor Coactivators in Cancer

 Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously. An example is phenylketonuria, a human disease that affects multiple systems but is caused by one gene defect.

abstract - Clinical Cancer Research

 Coactivators represent a large class of proteins that partner with nuclear receptors and other transcription factors to regulate gene expression. Given their pleiotropic roles in the control of transcription, coactivators have been implicated in a broad range of human disease states, including cancer. This is best typified by the three members of the steroid receptor coactivator (SRC) family, each of which integrates steroid hormone signaling and growth factor pathways to drive oncogenic gene expression programs in breast, endometrial, ovarian, prostate, and other cancers. Because of this, coactivators represent emerging targets for cancer therapeutics, and efforts are now being made to develop SRC-targeting agents, such as the SI-2 inhibitor and the novel SRC stimulator, MCB-613, that are able to block cancer growth in cell culture and animal model systems. Here, we will discuss the mechanisms through which coactivators drive cancer progression and how targeting coactivators represent a novel conceptual approach to combat tumor growth that is distinct from the use of other targeted therapeutic agents. We also will describe efforts to develop next-generation SRC inhibitors and stimulators that can be taken into the clinic for the treatment of recurrent, drug-resistant cancers. Clin Cancer Res; 22(22); 1–5. ©2016 AACR.

 

Index: October 2016 : Menopause

Current Issue : Menopause

 

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October 2016 - Volume 23 - Issue 10

Table of Contents Outline

Editorials

Hot flashes: avoiding the reductionist view Taylor, Hugh S. Purchase Access PDF + Favorites Request Permissions

The symptomatic menopause: the future is purchased by the present Shulman, Lee P. Purchase Access PDF + Favorites Request Permissions

The Woman's Health Initiative and one of many unintended consequences Simon, James A. Purchase Access PDF + Favorites Request Permissions

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Original Articles

Relationship between changes in vasomotor symptoms and changes in menopause-specific quality of life and sleep parameters Pinkerton, JoAnn V.; Abraham, Lucy; Bushmakin, Andrew G.; More Purchase Access Abstract PDF + Favorites Request Permissions

Characterizing the trajectories of vasomotor symptoms across the menopausal transition Tepper, Ping G.; Brooks, Maria M.; Randolph, John F. Jr; More Purchase Access Abstract PDF + Favorites Request Permissions

Prescribing of FDA-approved and compounded hormone therapy differs by specialty Constantine, Ginger D.; Archer, David F.; Graham, Shelli; More Open Access Supplemental Author Material Abstract PDF + Favorites Request Permissions

Effect of conjugated estrogens/bazedoxifene on postmenopausal bone loss: pooled analysis of two randomized trials Gallagher, J. Christopher; Palacios, Santiago; Ryan, Kelly A.; More Purchase Access Abstract PDF + Favorites Request Permissions

Most bothersome symptom in women with genitourinary syndrome of menopause as a moderator of treatment effects Pinkerton, JoAnn V.; Bushmakin, Andrew G.; Abraham, Lucy; More Purchase Access Abstract PDF + Favorites Request Permissions

An assessment of the safety and efficacy of a fractional CO2 laser system for the treatment of vulvovaginal atrophy Sokol, Eric R.; Karram, Mickey M. Purchase Access Abstract PDF + Favorites Request Permissions

Fractional microablative CO2 laser for vulvovaginal atrophy in women treated with chemotherapy and/or hormonal therapy for breast cancer: a retrospective study Pagano, Tiziana; De Rosa, Pasquale; Vallone, Roberta; More Purchase Access Abstract PDF + Favorites Request Permissions

Short-term effects of low-dose estradiol on endothelial function and blood viscosity in nondiabetic postmenopausal overweight women: a double-blind, placebo-controlled study Panazzolo, Diogo G.; da Silva, Lucia H.A.; Maranhão, Priscila A.; More Purchase Access Abstract PDF + Favorites Request Permissions

Physical fitness improvement in overweight postmenopausal women who do not lose fat mass in response to exercise training Myette-Côté, Étienne; Archambault-Therrien, Claudie; Brochu, Martin; More Purchase Access Abstract PDF + Favorites Request Permissions

Age at natural menopause in women on long-term methotrexate therapy for rheumatoid arthritis Banas, Tomasz; Hajdyla-Banas, Iwona; Pitynski, Kazimierz; More Purchase Access Abstract PDF + Favorites Request Permissions

Prevalence and association between objective signs and subjective symptoms of vaginal atrophy: the AGATA study Cagnacci, Angelo; Carbone, Maria M.; Palma, Federica; More Purchase Access Abstract PDF + Favorites Request Permissions

Sexual and reproductive healthcare utilization among women aged 40 to 49 in rural China Sun, Xiaoming; Sun, Yu; Zong, Zhanhong; More Purchase Access Abstract PDF + Favorites Request Permissions

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Review Article

Bone mass improved effect of icariin for postmenopausal osteoporosis in ovariectomy-induced rats: a meta-analysis and systematic review

Prognostic value of endometriosis in patients with stage I ovarian clear cell carcinoma: Experiences at 3 academic institutions

abstract:
Prognostic value of endometriosis in patients with stage I ovarian clear cell carcinoma: Experiences at three academic institutions

Highlights

• •OCCC patients with EAOC had significantly improved survival than those without EAOC.
• •EAOC was not an independent prognostic predictor for patients with stage I OCCC.
• •The intrinsic relationship between EAOC and OCCC warrants further investigation.

Objectives

To investigate the prognostic value of endometriosis in patients with stage I ovarian clear cell carcinoma (OCCC).

Methods

The medical records of patients with stage I OCCC who had undergone complete staging surgery followed by systemic chemotherapy were retrospectively reviewed.

Results

A total of 237 women were included in this study. Univariate analysis revealed that the patients with endometriosis-associated ovarian carcinoma (EAOC) had significantly improved recurrence-free survival (RFS) and overall survival (OS) than those without EAOC (5-year RFS: 91.4% vs. 73.0%, respectively, and 5-year OS: 97.5% vs. 89.9%). However, EAOC was not identified as a significant prognostic predictor in multivariate analysis. The potential risk factors determined to be associated with EAOC included the pretreatment CA-125 level, FIGO stage, lymphovascular space invasion (LVSI), and menopausal status (P < 0.001, P = 0.0031, P = 0.020, and P = 0.038, respectively).

Conclusions

Endometriosis was not independently associated with the prognosis of the OCCC patients, even when the tumor was confined to stage I. However, the intrinsic relationship between endometriosis and OCCC warrants further investigation.

Abbreviations:

OCCC (Ovarian clear cell carcinoma), RFS (recurrence-free survival), OS (overall survival), FIGO (Federation of Gynecology and Obstetrics), WHO (World Health Organization), LVSI (Lymphovascular space invasion), EAOC (Endometriosis-associated ovarian carcinoma)

Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer: (35 countries)

open access (pdf)

 Hypertension also seemed to be more common in ROSiA than in ICON7  or GOG-0218.

 Overall survival results are immature with events in only
23% of patients. Unfortunately, further long-term follow-up is
not planned within the framework of the study, as the ROSiA
safety study was designed with PFS as the primary efficacy
outcome rather than OS.
In summary, results from this large multinational
frontline study in ovarian cancer indicate that extended
bevacizumab-containing therapy is both tolerable and feasible.
The single-arm study design does not allow us to draw definitive
conclusions on the impact of treatment duration on efficacy;
however, the median PFS of 25.5 months is the longest
reported to date.

 Abstract

Objective: The aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer.

Patients and Methods: In this multinational prospective single-arm study (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IV or grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator's choice of 175 mg/m2 q3w or 80 mg/m2 weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety.

Results: Between December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1-50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7-27.6 months).

Conclusion: Extended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for frontline bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.

This is an open-access article

              Study Design and Patients
Generally, eligibility criteria were designed to recruit a
patient population similar to that enrolled in ICON7. Patients
had to be aged 18 years or older with Eastern Cooperative
Oncology Group performance status 0 to 2. Eligible patients
had histologically confirmed epithelial ovarian carcinoma,
fallopian tube carcinoma, or primary peritoneal carcinoma of
International Federation of Gynecology and Obstetrics
(FIGO) stage IIB to IV (any grade) or stage I to IIA (grade 3),
or clear cell carcinoma, or carcinosarcoma. Patients should
have already undergone maximal surgical debulking unless
they had inoperable stage III or IV disease. Unlike ICON7,
patients could be enrolled after neoadjuvant chemotherapy
and interval debulking surgery, with bevacizumab initiated
after surgery.

Histologic classification†
Serous 750 (73.5)
Endometrioid 90 (8.8)
Clear cell 68 (6.7)
Mucinous 23 (2.3)
Mixed 65 (6.4)
Adenocarcinoma NOS 88 (8.6)
Other 48 (4.7)

The Influence of Cyst Emptying, Lymph Node Resection and Chemotherapy on Survival in Stage IA and IC1 Epithelial Ovarian Cancer

abstract:
The Influence of Cyst Emptying, Lymph Node Resection and Chemotherapy on Survival in Stage IA and IC1 Epithelial Ovarian Cancer

Aim: To determine if survival in stage I ovarian cancer is influenced by cyst emptying, lymph node resection and chemotherapy.

Patients and Methods: A survival analysis of 607 patients with ovarian cancer in stage IA, IA with cyst emptying (IAempty) and IC1 was performed.

Results: There was no difference in five-year survival between IA (87%) and IC1 (87%) (p=0.899), between IA and IAempty (86%) (p=0.500) nor between IA+IAempty (87%) and IC1 without IAempty (84%) (p=0.527). Five-year survival rate (5YSR) was significantly higher after lymph node resection in stage IA (94% vs. 85%; p=0.01) and IA+IC1 (93% vs. 85%; p=0.004). In multivariate analysis, lymph node resection improved prognosis significantly for all sub-stages, whereas stage and chemotherapy did not affect survival.

Conclusion: In stage IA ovarian cancer, controlled cyst emptying without spill does not worsen prognosis. Lymph node resection is associated with improved survival in stage IA and IC1. Chemotherapy should only be offered where randomized controlled studies have shown a benefit.

What Characterizes Long-term Survivors of Recurrent Ovarian Cancer? Case Report and Review of the Literature

abstract:
What Characterizes Long-term Survivors of Recurrent Ovarian Cancer? Case Report and Review of the Literature

Background: Women with recurrent ovarian cancer have a poor prognosis and short survival. However, some women are long-term survivors and it is unclear whether they share specific common characteristics.

Case Report: We present the case of a 63-year-old woman with histologically-proven recurrent ovarian cancer and a survival time of 16 years after the diagnosis of recurrence. She underwent initial debulking surgery in 1994, followed by 6 cycles of adjuvant chemotherapy with cisplatin and paclitaxel. After recurrent disease was diagnosed by re-laparotomy in 2000, she underwent four lines of systemic chemotherapy from 2000 to 2009 (carboplatin/paclitaxel, topotecan, etoposide/treosulfan and liposomal doxorubicin) and four lines of endocrine therapy between 2002 and 2014 (tamoxifen, goserelin, tamoxifen and exemestane). In 2014, she underwent secondary debulking surgery and was tumor-free until 2015. Upon progression, she was then started on the fifth-line of endocrine therapy, fulvestrant, which was changed to the mTOR inhibitor everolimus in June 2016. In a PUBMED literature search, 360 cases of long-term survivors of recurrent ovarian cancer (LTSROC), defined as women with survival >5 years after the diagnosis of recurrence, were identified with a mean post-recurrence survival time of 7.5 years. Comparing the patient and therapy details of these women, we identified common characteristics of LTSROC, i.e. young age and optimal debulking at initial surgery, a long time span between first-line therapy and first recurrence and the combined use of optimal cytoreductive surgery and systemic chemotherapy.

Conclusion: LTSROC are rare, with 360 cases described in the literature. LTSROC are characterized by young age, low tumor stage, long recurrence-free interval and combined modality treatment with optimal cytoreductive surgery and systemic chemotherapy.

Tell America It's Great - YouTube (this is fun!)

#tellamericaitsgreat

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Kalie Strain1 hour ago

Thank you Canada, we needed that. We love you too.

Harrison Shone1 hour ago

Thanks Canada!

1

kinseymilkbone2 days ago

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21

Roel Hammerschlag1 hour ago

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4

This Is Fifty With Lil11 hours ago

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5

GinaZVlogTV6 hours ago

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5

Keep Florida Wild™1 hour ago

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1

RantWithJeff19 minutes ago

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