Abstract 5492
Background
Resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer drives mortality and despite new targeted therapies, resistance is the obstacle to progression-free survival. Fulvestrant (FUL), a selective estrogen receptor degrader (SERD) was approved in 2017 for fırst-line therapy of metaststic disease in postmenopausal women; however, acquired FUL-resistance in both fırst-line setting and in combination therapy with CDK4/6 inhibitor, palbociclib, has been observed clinically. The poor pharmacokinetics of FUL may contribute to acquired resistance.
Methods
Using structure-based design, we optimized: 1) novel SERDs bearing a basic side chain (B-SERDs) as an orally bioavailable and brain penetrant alternative to FUL; 2) novel pyridinone-based bromodomains and extra-terminal motif (BET) inhibitors to be used in combination with B-SERDs or FUL. Biochemical assays and growth inhibition of breast cancer cell lines, resistant to tamoxifen, and/or FUL, both in 2D and 3D cultures were used to optimize and select development candidates. Drug metabolism and pharmacokinetics(DMPK) demonstrated oral bioavailability and dose selection for validation in mouse xenograft models of endocrine resistant breast cancer.
Results
B-SERDs showed equivalence to FUL in cell culture models, with respect to ERα degradation and antiproliferative activity; and in contrast to FUL, were demonstrated to have good oral and brain bioavailability. A development candidate with improved DMPK characteristics was effective in endocrine-resistant ER+ xenograft models. Novel BET inhibitors, optimized for potency in binding to BRD4-BD1 and selectivity over the larger family of bromodomain containing proteins, inhibited growth of tamoxifen and FUL-resistant breast cancer cells.Optimized compounds showed superior in vitro activity to eight BET inhibitors in clinical trials. The optimized BET inhibitor was validated alone and in combination with B-SERD in endocrine-resistant xenograft models.
Conclusions
The combination of B-SERD with BET inhibitor provides a multi-targeted suppression of ER signaling that may extend progression-free survival and cdircumvent acquired resistance in metastatic ER+ breast cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Gregory R J Thatcher.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2459 - Does bevacizumab increase joint pain ? Preliminary results of BEVARTHRALGIA Study
Presenter: Vauleon Enora
Session: Poster Display session 1
Resources:
Abstract
4913 - Prostatic cancer androgen deprivation therapy and bone health in carcinoma prostate.
Presenter: Gouri Shankar Bhattacharyya
Session: Poster Display session 1
Resources:
Abstract
1352 - Patterns of care for patients with metastatic bone disease in solid tumors – a cross-sectional study (SAKK 95/16)
Presenter: Michael Mark
Session: Poster Display session 1
Resources:
Abstract
6002 - Infection-Related Mortality in Different Types of Cancers
Presenter: Mohamed Gouda
Session: Poster Display session 1
Resources:
Abstract
5643 - Survival Trends in Critically ill Oncology Patients: impact of patient’s eligibility to post-ICU chemotherapy
Presenter: Edith Borcoman
Session: Poster Display session 1
Resources:
Abstract
3097 - Development and validation of a multivariable prediction model for 6-month mortality in older cancer patients: the GeriAtrIc-Tumor Score of PrEdiction for Early Death (GAIT SPEED)
Presenter: Angeli Angeli
Session: Poster Display session 1
Resources:
Abstract
856 - A Longitudinal Tracking and Quantitative Assessment of Paclitaxel-Induced Peripheral Neurotoxicity
Presenter: Ayumu Matsuoka
Session: Poster Display session 1
Resources:
Abstract
1662 - Efficiency of controlled cryotherapy in prevention of chemotherapy induced peripheral neuropathy (CIPN)
Presenter: Trudi Schaper
Session: Poster Display session 1
Resources:
Abstract
2766 - The Validity of Evaluations for Chemotherapy-Induced Peripheral Neuropathy (CIPN)
Presenter: Teppei Yamada
Session: Poster Display session 1
Resources:
Abstract
5683 - Prevention of chemoradiation-related mucositis in patients with head and neck cancer using dexamethasone-based mouthwash: A phase II randomized double-blind, placebo-controlled study
Presenter: Naiyarat Prasongsook
Session: Poster Display session 1
Resources:
Abstract