Cancer cell metabolism is increasingly recognised as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small molecule ironomycin (AM5) reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial

The fundamental principle of precision oncology is centralized on identification of therapeutically exploitable targets that provides individual cancer patients an opportunity to make informed decisions on a personalized level. To facilitate and adopt such concepts within clinical practice, we have initiated a nation-wide, multi-institutional precision oncology screening program to examine and enroll

BRD4-cJUN-CCL2-TNFα axis disruption in basal-like pancreatic cancer restores a favorable phenotype.

Blinatumomab nonresponders have worse CD19-CAR response than responders or blinatumomab-naïve patients.

Highly complex genomic amplification arises from chromothripsis followed by circular recombination.

Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion

Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of promyelocytic leukemia (PML) nuclear

Immunotherapy has potential to prevent and treat metastatic breast cancer, but strategies to enhance immune-mediated killing of metastatic tumors are urgently needed. We report that a ligand-independent isoform of Ron kinase (SF-Ron) is a key target to enhance immune infiltration and eradicate metastatic tumors. Host-specific deletion of SF-Ron caused recruitment of lymphocytes to micrometastases,

Biliary tract cancer ranks among the most lethal human malignancies, representing an unmet clinical need. Its abysmal prognosis is tied to an increasing incidence and a fundamental lack of mechanistic knowledge regarding the molecular basis of the disease. Here, we show that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible toward transformation by activated PIK3CAH1047R but refractory

Natural killer (NK) cells and T cells are key effectors of antitumor immune responses and major targets of checkpoint inhibitors. In multiple cancer types, we find that the expression of Wnt signaling potentiator R-spondin genes (e.g., RSPO3 ) is associated with favorable prognosis and positively correlates with gene signatures of both NK cells and T cells. Although endothelial cells and cancer-associated

Myeloproliferative neoplasms (MPN) are chronic blood diseases with significant morbidity and mortality. Although sequencing studies have elucidated the genetic mutations that drive these diseases, MPNs remain largely incurable with a significant proportion of patients progressing to rapidly fatal secondary acute myeloid leukemia (sAML). Therapeutic discovery has been hampered by the inability of genetically

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization

The repression of repetitive elements is an important facet of p53's function as a guardian of the genome. Paradoxically, we found that p53 activated by MDM2 inhibitors induced the expression of endogenous retroviruses (ERV) via increased occupancy on ERV promoters and inhibition of two major ERV repressors, histone demethylase LSD1 and DNA methyltransferase DNMT1. Double-stranded RNA stress caused

Using a panel of cancer cell lines, we characterized a novel degrader of AKT, MS21. In mutant PI3K–PTEN pathway cell lines, AKT degradation was superior to AKT kinase inhibition for reducing cell growth and sustaining lower signaling over many days. AKT degradation, but not kinase inhibition, profoundly lowered Aurora kinase B (AURKB) protein, which is known to be essential for cell division, and induced

While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo . We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease

Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUAD) amenable to targeted therapy, transformation to small cell lung cancer (SCLC) is a recognized resistance mechanism. Defining molecular mechanisms of neuroendocrine (NE) transformation in lung cancer has been limited by a paucity of pre/posttransformation clinical samples. Detailed genomic, epigenomic

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers

Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered

Our knowledge of how clonal hematopoiesis relates to diverse health conditions has grown vastly over the past years, touching upon many specialties beyond cancer medicine. Given that clonal hematopoiesis can act as a precursor to overt disease in many settings, the promise of early intervention has garnered much attention. In this review, we discuss the state of clonal hematopoiesis research and outline

Growing evidence demonstrates that circulating tumor DNA (ctDNA) minimal residual disease (MRD) following treatment for solid tumors predicts relapse. These results suggest that ctDNA MRD could identify candidates for adjuvant therapy and measure response to such treatment. Importantly, factors such as assay type, amount of ctDNA release, and technical and biological background can affect ctDNA MRD

Summary: In this issue of Cancer Discovery , Penter and colleagues describe the results of applying the recently described technology of combined assay for transposase-accessible chromatin using sequencing and mitochondrial DNA sequencing in single cells from serial samples from nine patients with chronic lymphocytic leukemia. The naturally occurring barcodes, provided by mitochondrial DNA mutations

Summary: Lineage plasticity is an important, and likely underappreciated, mechanism of treatment resistance in lung cancer. Here, Quintanal-Villalonga and colleagues integrate results from multiomic analyses to provide key new insights into the biology of lineage plasticity. See related article by Quintanal-Villalonga et al., [p. 3028][1] . [1]: /lookup/volpage/11/3028?iss=12

Summary: Developing effective therapies in anti–PD-1–resistant melanoma is a key unmet need. The combination of pembrolizumab with the intralesional TLR9 agonist vidutolimod showed promise in this patient population with correlative analysis suggesting that patients with a “cold” tumor immune microenvironment may be the best patients to study further. See related article by Ribas et al., [p. 2998][1]

The gut microbiota drives hormone resistance in castration-resistant prostate cancer (CRPC).

Two distinct tumor microenvironment (TME) states exist in pancreatic cancer and are linked to patient outcome.

Dual-targeting CAR T cells show safety and efficacy in pediatric/young adult relapsed or refractory B-ALL.

Mutant clones in normal epithelium can limit the early formation of esophageal tumors in mice.

DNA methylation alterations facilitate cellular stress response and intratumoral heterogeneity.

MRgFUS-delivered trastuzumab demonstrated safety and efficacy in treating brain metastases.

Dual inhibition of BTK and IDO promotes monocytic lineage–derived dendritic cell differentiation.

Engineered bacteria increase intratumoral L-arginine which synergizes with immune checkpoint therapies.

E. faecalis is abundant in chronic hepatobiliary disease patients and induces liver tumorigenesis.

The microbiota controls mononuclear phagocytes in the tumor microenvironment through IFN-I signaling.

A collection of recently published news items.

Chimeric antigen receptor (CAR) T-cell therapy has had limited efficacy against solid tumors, but a CAR T-cell therapy targeting isoform 2 of the tight junction membrane protein claudin 18, preferentially expressed on stomach mucosal cells, showed acceptable safety and promising efficacy against advanced digestive system cancers in a phase I trial.

Ivosidenib extends overall survival in patients with previously treated, advanced cholangiocarcinoma whose disease harbors IDH1 mutations. Median overall survival was 10.3 months in patients who received the drug, versus 7.5 months in the placebo group. The difference was even larger—5.1 months—when researchers accounted for patient crossover into the treatment group.

According to a preclinical report, the investigational tyrosine kinase inhibitor BDTX-1535 may mitigate resistance to osimertinib, the standard of care for EGFR-mutant non–small cell lung cancer. It could also potentially treat central nervous system metastases, having shown preclinical efficacy in glioblastoma.

A tumor-penetrating bicyclic peptide that delivers a toxic payload may have finally unlocked the therapeutic potential of targeting EphA2. According to phase I trial data, BT5528 yielded clinical responses in three patients with ovarian and urothelial cancers—without any of the toxicity issues that have plagued other EphA2-directed therapeutic candidates.

Findings from a simulated pancreatic cancer trial indicate that some common eligibility criteria, including infectious comorbidities, disproportionately disqualify more Black than white patients from being enrolled. The researchers proposed alternative criteria, showing that the changes could eliminate the imbalance in eligibility.

After 12 years at the helm of the NIH, geneticist Francis Collins, MD, PhD, announced plans on October 5 to step down as the agency's director by the end of 2021.

Based on mounting evidence that tocilizumab improves survival in critically ill patients with COVID-19, the FDA granted it an emergency use authorization for COVID-19 treatment in June. Two months later, the agency added tocilizumab to its list of drug shortages, where it remains despite a slowly increasing supply.

See article, [p. 2998][1] . ![][2] Melanomas that lack CD8+ T cells or interferon signatures seldom respond to PD-1 blockade. Intratumoral injection of innate immune activators such as TLR9 agonists might induce interferon signatures and antitumor T cells, overcoming resistance to PD

Knockout of Cop1 inhibits M2 macrophage infiltration and enhances immunotherapy response in TNBC.

Autologous hematopoietic cell transplant (auto-HCT) decreases relapse and increases survival compared with CAR-T.

Flt3 and Npm1 mutations synergize to rewire the chromatin landscape in acute myeloid leukemia (AML).

A biologically informed sparse neural network, P-NET, revealed previously unknown potential drivers.

The adaptive immune system selects for inactivation of tumor suppressor genes in multiple cancer models.

Nuclear envelope (NE) disruptions induce DNA damage which increases tumor cell invasion.

A systematic analysis of patient data combined with molecular dynamics simulations and in vitro drug screens have revealed structure–function relationships that, in retrospective analyses, correctly identified drug sensitivity in patients with non–small cell lung cancer harboring atypical oncogenic EGFR mutations.

Results from phase II trials of two HER2-targeting agents, the antibody–drug conjugate trastuzumab deruxtecan and the HER2-targeting tyrosine kinase inhibitor poziotinib, indicate promising efficacy that could lead to new standards of care for HER2-mutant non–small cell lung cancer.

The Albert and Mary Lasker Foundation has bestowed its prestigious Lasker–Koshland Award for Special Achievement in Medical Science upon David Baltimore, PhD, president emeritus and distinguished professor of biology at the California Institute of Technology (Caltech) in Pasadena, and 1975 Nobel Laureate in Physiology or Medicine, calling him “one of the premier biomedical scientists of the last five

Patients with cancer are at high risk for complications and death from COVID-19 infections, but vaccination offers patients with solid tumors strong protection against SARS-CoV-2, including the Delta variant. Patients with hematologic malignancies, however, are less likely to mount a strong immune response to vaccination, possibly due to the natural history of the disease and to B cell–depleting therapies

Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple a-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on

BACE1 inhibition reprograms macrophages to promote their phagocytosis of cancer cells reducing glioblastoma progression.

Cryo-EM analysis uncovers the structure of the active, oncogenic HER2-HER3 heterodimer complex.

Combination of vibostolimab and pembrolizumab is well tolerated and has antitumor activity.

Preliminary findings from a first-in-human phase I/II trial of GEN1042, a bispecific antibody that simultaneously targets CD40 and 4-1BB on immune cells, suggest that this drug is well tolerated and active in patients with advanced solid tumors.

Ibrutinib treatment extended time to active disease in early stage chronic lymphocytic leukemia.

Patient survival and treatment response are correlated with 89Zr-pembrolizumab uptake.