Prognostic immune markers in esophageal cancer patients managed with trimodal therapy.

Background: Esophageal cancer (ESC) is an aggressive disease which often presents at an advanced stage. Despite trimodal therapy, 40-50% patients can develop metastatic disease by 18 months. Identification of patients at risk for metastatic spread is challenging with need for improved prognostication.

Separable Cell Cycle Arrest and Immune Response Elicited through Pharmacological CDK4/6 and MEK Inhibition in RASmut Disease Models.

The combination of CDK4/6 and MEK inhibition as a therapeutic strategy has shown promise in various cancer models, particularly in those harboring RAS mutations. An initial high-throughput drug screen identified high synergy between the CDK4/6 inhibitor palbociclib and the MEK inhibitor trametinib when used in combination in soft tissue sarcomas. In RAS mutant models, combination treatment with palbociclib and trametinib induced significant G1 cell cycle arrest, resulting in a marked reduction in cell proliferation and growth.

Real-World Experience among Elderly Metastatic Breast Cancer Patients Treated with CDK4/6 Inhibitor-Based Therapy.

The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study.

Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors.

The Extracellular Niche and Tumor Microenvironment Enhance KRAS Inhibitor Efficacy in Pancreatic Cancer.

Unlabelled: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective treatment options, highlighting the need for developing new therapeutic interventions. Here, we assessed the response to pharmacologic inhibition of KRAS, the central oncogenic driver of PDAC. In a panel of PDAC cell lines, inhibition of KRASG12D with MRTX1133 yielded variable efficacy in suppressing cell growth and downstream gene expression programs in 2D cultures.

Systemic infusion of TLR3-ligand and IFN-α in patients with breast cancer reprograms local tumor microenvironments for selective CTL influx.

Background: Presence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts the effectiveness of cancer immunotherapies. The ability of toll-like receptor 3 (TLR3) ligands, interferons (IFNs) and COX2 inhibitors to synergistically induce CTL-attracting chemokines (but not regulatory T cell (Treg)-attractants) in the TME, but not in healthy tissues, observed in our preclinical studies, suggested that their systemic application can reprogram local TMEs.

Methods: Six evaluable patients (33-69 years) with metastatic triple-negative breast cancer received six doses of systemic chemokine-modulating (CKM) regimen composed of TLR3 ligand (rintatolimod; 200 mg; intravenous), IFN-α2b (20 MU/m; intravenous) and COX2 inhibitor (celecoxib; 2×200 mg; oral) over 2 weeks.

Cancer takes many paths through G1/S.

In the commonly accepted paradigm for control of the mammalian cell cycle, sequential cyclin-dependent kinase (CDK) and cyclin activities drive the orderly transition from G1 to S phase. However, recent studies using different technological approaches and examining a broad range of cancer cell types are challenging this established paradigm. An alternative model is evolving in which cell cycles utilize different drivers and take different trajectories through the G1/S transition.

Determinants of response to CDK4/6 inhibitors in the real-world setting.

Despite widespread use and a known mechanism of action for CDK4/6 inhibitors in combination with endocrine therapy, features of disease evolution and determinants of therapeutic response in the real-world setting remain unclear. Here, a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS) and overall survival (OS). In this cohort of 280 patients, >90% of patients were treated with palbociclib in combination with either an aromatase inhibitor (AI) or fulvestrant (FUL).

PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies.

Background: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that target these kinases.

Methods: We utilized proteolysis-targeted chimeras (PROTACs) that are conjugated with palbociclib (Palbo-PROTAC) to degrade both CDK4 and CDK6.

Pharmacologically targeting KRAS in PDAC models: tumor cell intrinsic and extrinsic impact.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which new therapeutic interventions are needed. Here we assessed the cellular response to pharmacological KRAS inhibition, which target the central oncogenic factor in PDAC. In a panel of PDAC cell lines, pharmaceutical inhibition of KRAS allele, with MRTX1133 yields variable efficacy in the suppression of cell growth and downstream gene expression programs in 2D culture.

Galectin-3 expression in donor T cells reduces GvHD severity and lethality after allogeneic hematopoietic cell transplantation.

Abundant donor cytotoxic T cells that attack normal host organs remain a major problem for patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). Despite an increase in our knowledge of the pathobiology of acute graft versus host disease (aGvHD), the mechanisms regulating the proliferation and function of donor T cells remain unclear. Here, we show that activated donor T cells express galectin-3 (Gal-3) after allo-HCT.

Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer.

Unlabelled: Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent "long-tail" breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 ("EpiDrivers"), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells.

RB loss determines selective resistance and novel vulnerabilities in ER-positive breast cancer models.

The management of metastatic estrogen receptor (ER) positive HER2 negative breast cancer (ER+) has improved; however, therapeutic resistance and disease progression emerges in majority of cases. Using unbiased approaches, as expected PI3K and MTOR inhibitors emerge as potent inhibitors to delay proliferation of ER+ models harboring PIK3CA mutations. However, the cytostatic efficacy of these drugs is hindered due to marginal impact on the expression of cyclin D1.

Real-World Experience with CDK4/6 Inhibitors for Metastatic HR+/HER2- Breast Cancer at a Single Cancer Center.

Background: A study was initiated at Roswell Park Comprehensive Cancer Center to capture the real-world experience related to the use of CDK4/6 inhibitors (Ciclibs) for the treatment of metastatic hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-).

Patients And Methods: A total of 222 patients were evaluated who received CDK4/6 inhibitors in the period from 2015 to 2021. Detailed clinical and demographic information was obtained on each patient and used to define clinical and demographic features associated with progression-free survival on CDK4/6 inhibitor-based therapies.

Cancer cell cycle dystopia: heterogeneity, plasticity, and therapy.

The mammalian cell cycle has been extensively studied regarding cancer etiology, progression, and therapeutic intervention. The canonical cell cycle framework is supported by a plethora of data pointing to a relatively simple linear pathway in which mitogenic signals are integrated in a stepwise fashion to allow progression through G1/S with coordinate actions of cyclin-dependent kinases (CDK)4/6 and CDK2 on the RB tumor suppressor. Recent work on adaptive mechanisms and intrinsic heterogeneous dependencies indicates that G1/S control of the cell cycle is a variable signaling pathway rather than an invariant engine that drives cell division.

TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice.

Studies have shown that Nrf2 is one of the most common mutations found in human tumors. To elucidate how this genetic change contributes to lung cancer, we compared lung tumor development in a genetically-engineered mouse model (GEMM) with dual Trp53/p16 loss, the most common mutations found in human lung tumors, in the presence or absence of Nrf2. Trp53/p16-deficient mice developed combined-small cell lung cancer (C-SCLC), a mixture of pure-SCLC (P-SCLC) and large cell neuroendocrine carcinoma.

CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities.

Progression through G1/S phase of the cell cycle is coordinated by cyclin-dependent kinase (CDK) activities. Here, we find that the requirement for different CDK activities and cyclins in driving cancer cell cycles is highly heterogeneous. The differential gene requirements associate with tumor origin and genetic alterations.

Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer.

Purpose: We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with wild-type (RASwt), metastatic colorectal adenocarcinoma (mCRC).

Patients And Methods: In this phase Ib/II study, cetuximab was combined with pembrolizumab in patients with RASwt mCRC with ≥ one prior line of therapy for advanced disease. We analyzed baseline on-treatment tumor tissues for changes in the tumor microenvironment (TME), using flow cytometry and multispectral immunofluorescence.

Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity.

Cancer heterogeneity impacts therapeutic response, driving efforts to discover over-arching rules that supersede variability. Here, we define pan-cancer binary classes based on distinct expression of YAP and YAP-responsive adhesion regulators. Combining informatics with in vivo and in vitro gain- and loss-of-function studies across multiple murine and human tumor types, we show that opposite pro- or anti-cancer YAP activity functionally defines binary YAP or YAP cancer classes that express or silence YAP, respectively.

Correction: CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models.

[This corrects the article DOI: 10.18632/genesandcancer.24.

Concurrent Aspirin Use Is Associated with Improved Outcome in Rectal Cancer Patients Who Undergo Chemoradiation Therapy.

Background: The benefit of aspirin in rectal cancer during chemoradiation therapy (CRT) and the factors affecting its efficacy are not well characterized. We compared the outcomes of rectal patients undergoing neoadjuvant CRT based on aspirin use.

Methods: Patients undergoing CRT for rectal cancer from 2010 to 2018 were evaluated.

Functional Determinants of Cell Cycle Plasticity and Sensitivity to CDK4/6 Inhibition.

Intrinsic or acquired resistance to clinically approved CDK4/6 inhibitors has emerged as a major obstacle that hinders their utility beyond ER breast cancer. In this study, CDK4/6-dependent and -resistant models were employed to identify functional determinants of response to pharmacologic CDK4/6 inhibitors. In all models tested, the activation of RB and inhibition of CDK2 activity emerged as determinants of sensitivity.

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

Purpose: Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients.

A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy.

Metastatic pancreatic adenocarcinoma (mPC) has a poor prognosis. CDK4/6 is often deregulated in mPC due to loss, resulting in the loss of p16INK4a that inhibits CDK4/6. CDK4/6 inhibitor monotherapy is ineffective due to RAS-mediated activation of alternative pathways, including phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR).