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
4852 - Impact of routine screening and preemptive treatment on hepatitis B virus reactivation (HBVr) in patients receiving chemotherapy
Presenter: Celine Marty
Session: Poster Display session 1
Resources:
Abstract
5225 - The uptake, patient satisfaction and efficacy of scalp cooling among patients receiving chemotherapy in an Irish oncology day ward.
Presenter: William Maher
Session: Poster Display session 1
Resources:
Abstract
1901 - Placebo adverse events (AEs) in targeted and immune cancer therapy in the adjuvant and advanced setting: A systematic review and meta-analysis
Presenter: Diego Enrico
Session: Poster Display session 1
Resources:
Abstract
3258 - Reduced antibody levels and high seronegativity rates against vaccine preventable diseases pose a risk factor for infections in patients with solid and hematologic cancers
Presenter: Angela Guzek
Session: Poster Display session 1
Resources:
Abstract
3211 - Prognostic Factors Influencing Outcome After Therapy With Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin's Lymphoma
Presenter: Veselina Goranova - Marinova
Session: Poster Display session 1
Resources:
Abstract
4949 - Phase I Study of CC-90010 in Patients With Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL)
Presenter: Victor Moreno
Session: Poster Display session 1
Resources:
Abstract
2271 - Pretreatment coagulation factors related to prognosis in patients with natural killer/T cell lymphoma
Presenter: Yue Chai
Session: Poster Display session 1
Resources:
Abstract
4335 - Diffuse large B cell lymphoma in the elderly. A retrospective analysis of standard versus alternative treatments
Presenter: Irene Sillero
Session: Poster Display session 1
Resources:
Abstract
5117 - MIPI as a superior prognostic tool in Mantle Cell Lymphoma compared to monocyte-lymphocyte, neutrophil-lymphocyte and platelet-lymphocyte ratios
Presenter: Filipa Macedo
Session: Poster Display session 1
Resources:
Abstract
5135 - Dose adjustment of chemotherapy in aggressive lymphoma using automated and standardized analysis and evaluation of DNA double strand breaks
Presenter: Julia Schröder
Session: Poster Display session 1
Resources:
Abstract