Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast.

Invasive lobular carcinoma of the breast (ILC) are typically estrogen receptor α (ER)-positive and present with biomarkers of anti-estrogen sensitive disease, yet patients with ILC face uniquely poor long-term outcomes with increased recurrence risk, suggesting endocrine response and ER function are unique in ILC. We previously found specifically in ILC cells that ER is co-regulated by the DNA repair protein Mediator of DNA Damage Checkpoint 1 (MDC1). This novel MDC1 activity, however, was associated with dysfunction in the canonical DNA repair activity of MDC1, but absent typical features of DNA repair deficiency.

Lifetime fitness benefits of breeding site fidelity and low costs of inbreeding permit inbreeding tolerance in an avian cooperative breeder.

Inbreeding, or breeding with close relatives, often decreases individual fitness, but mate choice in many species can increase inbreeding risk. Inbreeding is more likely in species with limited dispersal, such as cooperative breeders where non-parental individuals-often offspring from previous broods-provide parental care and frequently breed close to home. We leverage 32 years of data from a population of Florida Scrub-Jays ( ), an avian cooperative breeder, to investigate whether mate choice, and its lifetime fitness outcomes, affects inbreeding tolerance.

Overcoming doxorubicin resistance in triple-negative breast cancer using the class I-targeting HDAC inhibitor bocodepsin/OKI-179 to promote apoptosis.

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important clinical challenge. Bocodepsin (OKI-179) is a small molecule class I histone deacetylase (HDAC) inhibitor that promotes apoptosis in TNBC preclinical models.

First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors.

(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients ( = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity.

Major cardiovascular adverse events in older adults with early-stage triple-negative breast cancer treated with adjuvant taxane + anthracycline versus taxane-based chemotherapy regimens: A SEER-medicare study.

Background: Triple-negative breast cancer (TNBC) is more aggressive as compared to other subtypes of breast cancer with characteristic metastatic patterns and a poor prognosis. The standard of care for early-stage TNBC is historically anthracycline and taxane-based chemotherapy (ATAX). Despite the effectiveness of this regimen, anthracyclines carry a small but important risk of cardiotoxicity, which is specifically a concern in the older population.

Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy.

Histone deacetylase inhibitors (HDACi) are currently being explored for the treatment of both solid and hematological malignancies. Although originally thought to exert cytotoxic responses through tumor-intrinsic mechanisms by increasing expression of tumor suppressor genes, several studies have demonstrated that therapeutic responses depend on an intact adaptive immune system: particularly CD8 T cells. It is therefore critical to understand how HDACi directly affects T cells in order to rationally design regimens for combining with immunotherapy.

The emergence of targeted therapy for HER2-low triple-negative breast cancer: a review of fam-trastuzumab deruxtecan.

Introduction: Metastatic triple-negative breast cancer (TNBC) is an aggressive sub-type of breast cancer. Despite recent advances, metastatic TNBC remains difficult to treat with limited targeted treatment options. Fam-trastuzumab deruxtecan (T-DXd), is a novel antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) and is composed of a unique linker bound to the topoisomerase I inhibitor DXd.

Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer.

Purpose: To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC).

Patients And Methods: Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.

Phase II trial of fulvestrant plus enzalutamide in ER+/HER2- advanced breast cancer.

This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2- breast cancer (BC). Eligible patients were women with ECOG 0-2, ER+/HER2- measurable or evaluable metastatic BC. Prior fulvestrant was allowed.

Clinical outcomes of adjuvant taxane plus anthracycline versus taxane-based chemotherapy regimens in older adults with node-positive, triple-negative breast cancer: A SEER-Medicare study.

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with an aggressive clinical course. Adjuvant chemotherapy reduces the risk of recurrence and improves survival in patients with node-positive TNBC. The benefit of anthracycline plus taxane (ATAX) regimens compared with non-anthracycline-containing, taxane-based regimens (TAX) in older women with node-positive TNBC is not well characterised.

BMS-986158, a Small Molecule Inhibitor of the Bromodomain and Extraterminal Domain Proteins, in Patients with Selected Advanced Solid Tumors: Results from a Phase 1/2a Trial.

This phase 1/2a, open-label study (NCT02419417) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158, a selective bromodomain and extraterminal domain (BET) inhibitor. Dose escalation was performed with 3 BMS-986158 dosing schedules: A (5 days on, 2 days off; range, 0.75-4.

A dose regimen-finding study to evaluate the safety, tolerability, pharmacokinetics, and activity of oratecan in subjects with advanced malignancies.

Purpose: Irinotecan is a commonly used chemotherapeutic in solid tumor malignancies. Oratecan is an investigational product comprised of encequidar methanesulfonate, a novel minimally absorbed P-glycoprotein pump inhibitor, and irinotecan. This study sought to determine the maximum tolerated dose (MTD) of oratecan in patients with advanced malignancies.

A phase Ib study of Oraxol (oral paclitaxel and encequidar) in patients with advanced malignancies.

Purpose: Oraxol is an oral formulation of paclitaxel administered with a novel, minimally absorbed P-glycoprotein inhibitor encequidar (HM30181A). This phase Ib study was conducted to determine the maximum-tolerated dose (MTD) of Oraxol administered at a fixed dose for up to 5 consecutive days in patients with advanced malignancies.

Methods: Part 1 of this study utilized a 3 + 3 dose-escalation design to determine the MTD of oral paclitaxel 270 mg plus oral encequidar 15 mg administered daily.

Sacituzumab govitecan as second-line treatment for metastatic triple-negative breast cancer-phase 3 ASCENT study subanalysis.

Patients with triple-negative breast cancer (TNBC) who relapse early after (neo)adjuvant chemotherapy have more aggressive disease. In the ASCENT trial, sacituzumab govitecan (SG), an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a hydrolyzable linker, improved outcomes over single-agent chemotherapy of physician's choice (TPC) in metastatic TNBC (mTNBC). Of 468 patients without known baseline brain metastases, 33/235 vs 32/233 patients (both 14%) in the SG vs TPC arms, respectively, received one line of therapy in the metastatic setting and experienced disease recurrence ≤12 months after (neo)adjuvant chemotherapy.

First-in-Human Dose-Escalation Study of Cyclin-Dependent Kinase 9 Inhibitor VIP152 in Patients with Advanced Malignancies Shows Early Signs of Clinical Efficacy.

Purpose: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor.

Patients And Methods: Adults with solid tumors or aggressive non-Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined.

Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors.

Histone deacetylases (HDACs) play critical roles in epigenomic regulation, and histone acetylation is dysregulated in many human cancers. Although HDAC inhibitors are active in T-cell lymphomas, poor isoform selectivity, narrow therapeutic indices, and a deficiency of reliable biomarkers may contribute to the lack of efficacy in solid tumors. In this article, we report the discovery and preclinical development of the novel, orally bioavailable, class-I-selective HDAC inhibitor, OKI-179.

Evaluating anthracycline + taxane versus taxane-based chemotherapy in older women with node-negative triple-negative breast cancer: a SEER-Medicare study.

Purpose: Adjuvant chemotherapy reduces recurrence in early-stage triple-negative breast cancer (TNBC). However, data are lacking evaluating anthracycline + taxane (ATAX) versus taxane-based (TAX) chemotherapy in older women with node-negative TNBC, as they are often excluded from trials. The purpose of this study was to evaluate the effect of adjuvant ATAX versus TAX on cancer-specific (CSS) and overall survival (OS) in older patients with node-negative TNBC.

Tackling metastatic triple-negative breast cancer with sacituzumab govitecan.

Metastatic triple-negative breast cancer (TNBC) is an aggressive cancer with poor survival that is difficult to treat due to a lack of targeted options. Conventional therapies targeting hormone receptors (HR) and human epidermal growth factor 2 (HER2) are ineffective and often chemotherapy is standard-of-care. Sacituzumab govitecan is an antibody drug conjugate (ADC) comprised of an active metabolite of irinotecan, SN-38, bound to a humanized monoclonal antibody targeting trophoblastic cell-surface antigen 2 (Trop-2).

A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation.

Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination.

Patients And Methods: Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m) or paclitaxel monotherapy in cycle 1.