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
5437 - Salivary cytokines and oral mucosa cells apoptosis in patients during hematopoietic cell transplantation: possible relationship with oral mucositis
Presenter: Luciana Corrêa
Session: Poster Display session 1
Resources:
Abstract
1483 - A randomized trial of sodium alginate prevention of radiation-induced esophagitis in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy: OLCSG1401
Presenter: Toshihide Yokoyama
Session: Poster Display session 1
Resources:
Abstract
2047 - Taste and smell alterations (TSAs) in patients (pts) with stage II-III colon cancer (CC): a pilot within the PROTECT study
Presenter: Jeroen Derksen
Session: Poster Display session 1
Resources:
Abstract
5984 - Clinical characteristics are associated with acupuncture treatment response for xerostomia in cancer patients
Presenter: Wenli Liu
Session: Poster Display session 1
Resources:
Abstract
2845 - Psychosocial Distress of Adolescent and Young Adults with Cancer at Diagnosis: A Case-Matched Retrospective Cohort of 2045 Patients in British Columbia.
Presenter: Alannah Smrke
Session: Poster Display session 1
Resources:
Abstract
724 - Accuracy of distress thermometer to measure cancer-related mood disorders in Chinese patients with cancer
Presenter: Sudip Thapa
Session: Poster Display session 1
Resources:
Abstract
2357 - Modalities of biosimilar filgrastim use in clinical practice in >1000 patients receiving chemotherapy regimens with a rest period of ≤14 days: the TOPAZE study
Presenter: Jean Marc Phelip
Session: Poster Display session 1
Resources:
Abstract
1426 - The Effect of Increasing Doses of Pegfilgrastim (Peg) on Thrombocytopenia (T) in Breast Cancer (BC) Patients (pts) Receiving Taxotere (Doc), Doxorubicin, Cyclophosphamide (TAC) and Plinabulin (Plin)
Presenter: Douglas Blayney
Session: Poster Display session 1
Resources:
Abstract
712 - The use of intravenous ferric carboxymaltose without erythropoiesis-stimulating agents in the treatment of anemia in cancer patients undergoing chemotherapy with or without radiotherapy
Presenter: Hikmat Abdel-Razeq
Session: Poster Display session 1
Resources:
Abstract
1496 - Randomized, double-blind, cross-over Phase I study comparing pharmacokinetics, pharmacodynamics, safety and immunogenicity of a biosimilar pegfilgrastim with EU and US references
Presenter: Maria Velinova
Session: Poster Display session 1
Resources:
Abstract