Volume 2 Issue 1, January 2021

Inhibition of the anti-apoptotic protein BCL-2 has emerged as a highly effective treatment for acute myeloid leukemia; approved lower-intensity venetoclax combination therapies are now being rapidly incorporated into an improved standard of care for this cancer. Here we recount an abbreviated history of venetoclax for acute myeloid leukemia, focusing on a selection of key studies along the path from development into the clinic.

Recent preclinical and clinical research has led to exciting advances related to high-grade serous ovarian cancer, from examining its cellular origins to gaining insight into DNA-damage-repair mechanisms that may be leveraged for therapies. Furthermore, studies have demonstrated clinical benefit for inhibition of the polymerase PARP and modulation of the cell cycle, and have identified molecular features related to therapeutic response.

Precision oncology trials based on cancer biomarkers have the potential to improve outcomes by guiding the optimal choice of therapies for patients. For this to be truly achieved, computational methods such as virtual molecular tumor boards, dynamic precision medicine and digital twins are needed to support cohort selection and trial enrollment at scale.

Immunostimulatory agents such as Toll-like receptor (TLR) agonists have shown promising antitumor efficacy but are associated with therapy-related toxicities when delivered systemically. Immune-stimulating antibody conjugates are now shown to deliver TLR agonists with potent preclinical antitumor activities.

Chronic pancreatitis is a risk factor for pancreatic cancer; however, the mechanisms underlying cellular susceptibility to oncogenic transformation are complex. A recent study reports a damage-associated progenitor cell state, controlled by the transcription factors KLF5 and members of the AP-1 family, that initiates tumorigenesis in mouse models of pancreatic cancer in which the proto-oncogene KRAS is altered.

The diversity of tumor cell responses to cyclin-dependent kinase 4/6 (CDK4/6) inhibition in breast cancer is a question not yet fully addressed. A recent study defines the effects of CDK4/6 inhibition on chromatin organization and shows that remodeling of the cancer cell epigenome mediates some of the key biological effects of these targeted therapy agents.

Alonso and colleagues develop immune-stimulating antibody conjugates capable of specific delivery of TLR7/8 agonists to tumors, which induces durable antitumor immunity.

Goel and colleagues show that CDK4/6 inhibition induces global chromatin changes mediated by AP-1 factors, which mediate key biological and clinical effects in breast cancer.

David and colleagues uncover an inflammation-activated, progenitor-derived enhancer network hijacked by mutant Kras during pancreatic cancer initiation.

Mehta et al. show that PARP inhibition induces CSF1R-dependent immune-suppressive macrophages, and that its blockade restores PARP inhibitor efficacy and stimulates CD8⁺ T cell-dependent antitumor immunity in triple-negative breast cancer.

Fan and colleagues report that inhibition of PAK4 normalizes the tumor vascular microenvironment and sensitizes glioblastomas to CAR-T cell immunotherapy.

Ferrando and colleagues identify FYN–TRAF3IP2 as a recurrent oncogenic gene fusion that promotes angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified through the activation of NF-κB signaling.

Westermann and colleagues define four subtypes of neuroblastoma based on super-enhancer profiles in primary patient samples, which could be linked to distinct clinical outcomes and cell identity characteristics.