Use of ctDNA can effectively guide panitumumab rechallenge in metastatic colorectal cancer.

Multicellular dynamics, including neoadjuvant treatment-associated changes, were uncovered in PDAC.

An organoid-based, 3D imaging-transcriptomic platform was developed to investigate immunotherapy modes of action.

Whole brain invasion of glioblastoma (GB) is driven by single GB cells with neuronal features.

President Joe Biden has chosen Monica Bertagnolli, MD, a renowned surgical oncologist, group chair of the Alliance for Clinical Trials in Oncology, and former president of the American Society of Clinical Oncology, to be the 16th director of the NCI. She will be the first woman to hold the position since the agency's founding in 1937. The news was greeted with excitement and praise from cancer researchers

According to new data from the phase III IMpower010 trial, adjuvant atezolizumab improves overall survival compared with best supportive care for some patients with operable non-small cell lung cancer. These results build on previous study findings, in which the immune checkpoint inhibitor, given after surgery and adjuvant chemotherapy, was shown to significantly decrease the likelihood of disease

BCL10, a key activator of NF-κB downstream of oncogenic B-cell receptor signaling, is mutated in nearly 40% of the BN2/C1 genetic subtype of diffuse large B-cell lymphoma, but how these mutations function to augment signaling and their relevance to targeted precision medicine agents remains unclear. In this issue of Cancer Discovery, Xia and colleagues demonstrate distinct mechanisms of oncogenic signaling

In this issue of Cancer Discovery, Drewes and colleagues demonstrate a surprising role for the common gut pathogen Clostridioides difficile in driving colorectal cancer in preclinical models through the bacterial toxin-dependent reprogramming of the epithelial and immune compartments. See related article by Drewes et al., p. 1873 (3).

Biomarkers guiding the neoadjuvant use of immune checkpoint inhibitors (ICBs) are needed for patients with localized muscle invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression

Cancer cell-derived Col1 homotrimers regulate the PDAC microbiome and block T-cell infiltration.

AKT inhibits the metabolic enzyme PANK4 to promote the de novo synthesis of coenzyme A (CoA).

Survival benefit and a manageable safety profile were observed with G47Δ in patients with glioblastoma.

Patients on ICI therapy rarely experience life-threatening myocarditis, but little is currently known about the risk of other major adverse cardiac events (MACE) in this population. A retrospective study finds that 10% of patients, mostly with advanced cancers, experience MACE, with those with preexisting poor cardiovascular health being at greater risk.

Addition of genetic risk score to prediction models improves obesity risk prediction in adult survivors of childhood cancer.

249C was identified as a selective Ras-mutant cytotoxic agent that binds to and inhibits V-ATPase.

The cGAS-STING axis drives IL6 signaling to enable survival despite chromosomal instability (CIN).

Immune-mediated skewing of MHC-I allele frequency occurs in calreticulin-mutant myeloproliferative neoplasms.

Patients with refractory or relapsed multiple myeloma usually develop resistance to the two approved BCMA-targeting chimeric antigen receptor (CAR) T cells. A preliminary study of a new CAR T-cell therapy that zeroes in on the GPRC5D protein on multiple myeloma cells suggests that this approach is safe and effective. All 10 patients treated with the GPRC5D-targeting cells showed responses.

CD8+ T cell-intrinsic androgen receptor (AR) signaling promotes sex-biased antitumor immunity.

Androgen receptor (AR) expression increases upon BRAF/MEK inhibitor treatment, promoting resistance.

The developed RPS-5 response prediction scheme was more predictive of pathologic complete response.

ADAR1 binds endogenous Z-RNA and masks the immunotherapeutic potential of ZBP1-induced necroptosis.

A cancer vaccine targeting MICA/B was developed that induces T-cell and NK-cell activation.

XIST controls homeostasis in mammary stem cells, balancing self-renewal and differentiation.

Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of mutated pre-leukemic cells. Individuals with CH are at an increased risk of developing hematopoietic malignancies. Here, we describe a novel animal model carrying a recurrent TET2 missense mutation, frequently found in CH and leukemic patients. In a fashion similar to CH, animals show signs of disease

Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adaptor of a Cullin-3 RING E3 ubiquitin ligase complex responsible for degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations were identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or

Chimeric Antigen Receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two-thirds of patients fail this treatment. Resistance to apoptosis is a key feature of cancer cells that associates with treatment failure. In 87 NHL patients treated with anti-CD19 CART, we found that chromosomal alteration of BCL-2

Selective inhibitors of K-Ras(G12S) mutations were developed that suppress oncogenic signaling.

Tumor-derived lactate disrupts pyruvate metabolism and cytotoxic function of antitumor CD8+ T cells.

Baseline plasma L-Arginine (ARG) levels can predict response to immune checkpoint inhibitors (ICI).

Multiple dominant somatic populations are present in ctDNA, with AR alterations driving treatment resistance.

Contrasting γδ T-cell function in tumors is dependent on TCR-Vγδ gene usage in both humans and mice.

Anti-cancer therapies have been limited by emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error-prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells

Use of an implantable microdevice identified drug combinations that improve therapeutic efficacy in tumors.

Novel germline loci were associated with the risk of clonal hematopoiesis (CH) within the UK Biobank.

pCSI improved central nervous system progression-free survival of LM as compared to standard of care.

A 4D live imaging system identified LGR5+ p27+ cancer stem cells that persist after chemotherapy and contribute to disease relapse.

Combined arginine depletion, GCN2 kinase inhibition, and senolytic therapy reduces HCC growth.

The confirmation of the HER2-low paradigm is expected to have a major impact in breast oncology. About half of all breast cancers harbor HER2-low expression, which can be targeted with the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), leading to a relevant survival benefit in the metastatic setting. Given this observation, treatment algorithms for both hormone receptor-positive

Intrahepatic cholangiocarcinoma (iCCA) exhibits extensive intratumoral heterogeneity and extremely high mortality rate. Here, we performed WES, RNA-seq, TCR-seq and multiplexed immunofluorescence on 207 tumor regions from 45 iCCA patients. Over half of iCCA displayed intratumoral heterogeneity of immune infiltration, and iCCA were classified into sparsely, heterogeneously, and highly infiltrated subgroups

Multicellularity was a watershed development in evolution. However, it also meant that individual cells could escape regulatory mechanisms that restrict proliferation at a severe cost to the organism: cancer. From the standpoint of cellular organization, evolutionary complexity scales to organize different molecules within the intracellular milieu. The recent realization that many biomolecules can

Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic

The NCI and Cancer Research UK have unveiled the first four winners of Cancer Grand Challenges awards. The teams will probe cancer cachexia, extrachromosomal DNA, CAR T cells for childhood solid tumors, and possible mechanisms of carcinogenesis. Each team received a 5-year, $25 million grant.

Determination of the SHOC2-PP1C-RAS structure uncovers the mechanism of substrate specificity for RAF.

CD8+ T cells that respond to neoadjuvant immunotherapy express tissue-resident memory gene programs.

The m5c and f5c RNA modifications support mitochondrial mRNA translation promoting metastasis.

The American Association for Cancer Research (AACR) Project GENIE is an international pan-cancer registry with the goal to inform cancer research and clinical care worldwide. Founded in late 2015, the milestone GENIE 9.1-public release contains data from >110,000 tumors from >100,000 people treated at 19 cancer centers from USA, Canada, the United Kingdom, France, Netherlands, and Spain. Here, we demonstrate

Small cell lung cancer is the most fatal form of lung cancer, with dismal survival, limited therapeutic options and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of small cell lung cancer (SCLC) sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation

Infusion of an oncolytic virus followed by radiotherapy led to responses and prolonged survival in patients with DIPG.

Pancreatic cancer cellular heterogeneity is enforced via paracrine signaling from mesenchymal cells.

Clinically significant genomic alterations were identified in pediatric tumors using molecular tumor profiling.

Ellegast and colleagues show that monocytic acute myeloid leukemias (AML), enriched in inflammatory and immune gene sets, exploit a transcriptional repressor-namely, IRF2BP2-to mitigate their cell-intrinsic inflammatory output and ensure their maintenance. IRF2BP2 ablation results in heightened inflammatory signals that reach a set point that triggers apoptotic AML cell death in an NF-κB-IL1β-dependent

In this issue, Hu and colleagues unveil that IFNα administration combined with anti-PD-1 therapy can potentiate murine and human CD8+ T-cell antitumor response in hepatocellular carcinoma, highlighting a novel therapeutic strategy for hepatocellular carcinoma. See related article by Hu et al., p. 1718 (6) .

The lack of clinical activity from various immune-checkpoint blockade approaches in mismatch repair- proficient (MMRp) colorectal cancer has demonstrated a critical need for novel approaches. In this issue, Crisafulli and colleagues provide proof of concept for the induction of hypermutability through the use of temozolomide as a potential pathway for enabling a productive anti-PD-1 immune response

Social media (SoMe) platforms have the ability to strengthen the oncology community, leading to intellectual connections that with time develop into friendships. SoMe has immense potential in all areas of medicine, and SoMe in oncology is proof of this, raising awareness about clinical trials, promoting cancer prevention techniques, amplifying oncology information, enabling diverse viewpoints into

The FDA has proposed a ban on menthol flavoring in cigarettes. If enacted, the prohibition would increase smoking cessation rates and decrease first-time tobacco use, in turn drastically reducing smoking-related cancer deaths.

Polycomb Repressive Complex 2 (PRC2) has oncogenic and tumor suppressor roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2 inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted

Low expression of cBAF components and MYC support a pro-memory CD8+ T-cell fate decision.

Depleting components of the cBAF chromatin remodeling complex improves antitumor T-cell function.

Driver mutations were identified in cryptic splice regions, 5' UTRs, and rarely mutated genes.