As the COVID-19 pandemic worsens, the clinical cancer community is grappling with how to continue providing access to experimental but potentially lifesaving therapies while keeping immunocompromised patients safe. To that end, cancer centers are making changes to their clinical trial programs, while pharmaceutical companies are deciding how—or whether—trials should continue.

Chlorotoxin, a small peptide component of scorpion venom, may help pinpoint glioblastoma cells for destruction when engineered into a chimeric antigen receptor T-cell therapy. The concept has shown efficacy in mice, without off-target toxicity, and will soon be assessed in patients.

See article, [p. 526][1] . ![][2] Approximately 7% of estrogen receptor–positive (ER+) breast cancers harbor mutations in AKT1 (most often E17K) that cause PI3K-pathway activation. However, due to the rarity of this genomically defined breast cancer subgroup, the potential

Summary: In this issue, Smyth and colleagues investigate the natural history of AKT1 -mutant metastatic breast cancer using the AACR Project GENIE, a novel research platform comprised of real-world, clinicogenomic data. A rare subset of tumors, AKT1 -mutant breast cancers demonstrated similar clinical and demographic characteristics and overall survival as AKT1 –wild-type tumors, but a longer duration

Summary: In this issue, Singh and colleagues describe a novel tumor-intrinsic mechanism of resistance to chimericantigen receptor (CAR) T-cell therapy targeting CD19 in B-cell malignancies. They show that reduced expression of death receptor genes in the tumors mediates resistance to killing by CAR T cells, leads to progressive CAR T-cell dysfunction, and is associated with unfavorable clinical outcome

Summary: In this issue of Cancer Discovery , Sodir and colleagues employ a pancreatic ductal adenocarcinoma mouse model with mutant KRAS and inducible MYC to demonstrate that MYC acts as a reversible driver of malignant tumor progression. Abrogation of MYC triggers rapid regression and disassembly of the ensemble tumor through both cancer cell–intrinsic and cancer cell–extrinsic mechanisms, providing

RET alterations have been characterized as oncogenic drivers in multiple cancers. The clinical validation of highly selective RET inhibitors demonstrates the utility of specific targeting of aberrantly activated RET in patients with cancers such as medullary thyroid cancer or non–small cell lung cancer. The remarkable responses observed have opened the field of RET-targeted inhibitors. In this review

The therapeutic armamentarium of acute myeloid leukemia (AML) has rapidly expanded in the past few years, driven largely by translational research into its genomic landscape and an improved understanding of mechanisms of resistance to conventional therapies. However, primary and secondary drug resistance remains a substantial problem for most patients. Research into the mechanisms of resistance to

AKT inhibitors have promising activity in AKT1 E17K-mutant estrogen receptor (ER)-positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of matched AKT1 E17K-mutant (n=153) and -wildtype (n=302) metastatic breast

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated acute myeloid leukemia (AML) patients. However, upfront resistance as well as relapse following initial response demonstrate the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax + azacitidine in AML patients correlate closely with developmental

Primary resistance to CD19-directed chimeric antigen receptor T cell therapy (CART19) occurs in 10-20% of patients with acute lymphoblastic leukemia (ALL), however the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by

Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples show relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity and dismal prognosis. We show that acute activation of Myc in indolent PanIN epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune cell types and trigger transition to pancreatic

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic Kras in pro-tumorigenic signaling interactions between cancer cells and host cells. We show that Kras* drives cell autonomous expression of type I cytokine receptor complexes (IL2ry-IL4ra and IL2ry-IL13ra1) in

The Pan-Cancer Analysis of Whole Genomes project-the largest investigation of whole tumor genomes to date-has laid bare characteristic DNA aberrations responsible for cancer's development and helped unravel mutational processes that shape tumor evolution.

The recently approved federal budget for the current fiscal year includes a $297 million funding boost for the NCI, allowing it to fund more than 125 additional competing grants. Although the move reverses a decade of decreases in R01 paylines, competition for grants is expected to remain intense.

Angiosarcoma Project researchers have uncovered some details about the molecular underpinnings of angiosarcoma, pointing to potential therapeutic options. Their work also suggests that a research model based on direct patient participation can overcome common barriers to studying rare diseases.

Previously unidentified breast cancer subtypes that may be linked to prognosis were identified using imaging mass cytometry, a recently invented and rapidly developing technique that allows spatial relationships among cells expressing selected markers to be determined.

A collection of recently published news items.

Antoni Ribas, MD, PhD, discusses the biological discoveries that have led to new therapies for melanoma-and the future of treatment for the disease.

Having shown preclinical promise, the first clinical data are now in on natural killer cells equipped with a chimeric antigen receptor targeting CD19. Albeit in a small number of patients so far, the experimental immunotherapy has elicited a high response rate with little to no toxicity.

In response to glucose starvation, AMPK inhibited lipid peroxidation-associated ferroptosis.

The anti-HER2-drug conjugate trastuzumab deruxtecan (T-DXd) was effective in HER2-low breast cancer.

In a phase Ib trial, osimertinib plus savolitinib showed efficacy in non-small cell lung cancer.

Group 2 innate lymphoid cells (ILC2) exerted antitumor effects in pancreatic adenocarcinomas.

PD-1 depletion or nivolumab treatment dampened morphine antinociception in mice and rhesus macaques.

Antibody-peptide epitope conjugates (APEC) can reprogram surface antigenicity of tumor cells.

Glycolysis was downregulated in normal but not transformed cells upon transfer to softer substrates.

Metastatic cells were remniscient of earlier developmental stages than primary tumor cells.

A lentiviral-barcoding approach using mouse embryonic cells allows driver-mutation identification.

The structure of CD20 with the antibody drug rituximab showed the binding mode and 2:2 stoichiometry.

Structural analyses showed that HPF1 contributed amino acid residues to the PARP1/2 active site.

NUAK1 inhibition caused buildup of nonproductive stalled transcription complexes in high-MYC cells.

In a draft guidance, the FDA urges researchers to take steps to increase enrollment of adults age 65 and older in clinical trials of investigational of cancer drugs. Noting that a drug's risk–benefit profile can vary significantly across age groups, the FDA recommends including older adults in early-phase studies and modifying trial designs and recruitment strategies to make it easier for them to participate

As cancer researchers shutter their labs to comply with COVID-19–related work restrictions, some are turning their attention, resources, and technical know-how to the challenge of tackling the deadly coronavirus.

Patients with HPV16+ cervical cancer and high T-cell responses to an HPV16 vaccine survived longer.

Inhibition of BET protein bromodomains BD1 and BD2 produces unique phenotypes in disease models.

Neoantigen-expressing pancreatic cancers had hastened progression and poor immunotherapy response.

The FGFR2b inhibitor bemarituzumab was effective in high-FGFR2b gastroesophageal adenocarcinoma.

Human macrophages equipped with chimeric antigen receptor constructs infiltrate solid tumors, ingest malignant tissue, and stimulate adaptive immunity in mouse models. Several new biotech companies are racing to bring the technology into clinical trials.

Amplification and oncogenic mutations of ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADCs) ado-trastuzumab emtansine (T-DM1) and

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2 -mutant solid tumors from a phase I trial ([NCT02564900][1]). Most common (>50%) treatment-emergent

Since 2018, the FDA has required that U.S. clinical trial results be reported to clinicaltrials.gov within a year of trial completion, but this mandate is often ignored. A recent study found that less than half of U.S. trials submitted results to the site by the deadline. Industry-led trials were the most likely to be reported on time.

As COVID-19 continues to surge, cancer scientists engaged in basic research face unique challenges. At centers throughout the United States, investigators are confronting difficult decisions about which experiments to continue, while securing supplies and creating contingency plans for a complete shutdown.

MYC is implicated in the development and progression of Pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumour development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arising in mice from an approximation of MYC trisomy. We show that this level of MYC alone

Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production. This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport

Tumor-derived retinoic acid promotes monocyte differentiation into immunosuppressive macrophages.

T cell–expressed PD-L1 exerts tolerogenic effects on tumor immunity in pancreatic cancer.

Monoubiquitinated FANCI and FANCD2 constitute the ID complex, which forms a sliding clamp on DNA.

LGR5− cells seed colorectal cancer metastases and produce stemlike LGR5+ outgrowth-promoting cells.

Thermo Fisher Scientific announced plans in March to acquire Qiagen in a $11.5 billion deal that could bring morediagnostic offeringsand sample-preparation technologies to one of the world's leading manufacturers of scientific instruments, research services, and laboratory consumables.

Insufficient reactivity against cells with low antigen density has emerged as an important cause of CAR resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and the CAR construct in axicabtagene-ciloleucel (CD19-CD28z) outperforms that in tisagenlecleucel (CD19-4-1BBz) against antigen low

Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that recurrent disease

Mutations in protein-coding genes are well established as the basis for human cancer, yet it remains elusive how alterations within non-coding genome, a substantial fraction of which contain cis-regulatory elements (CREs), contribute to cancer pathophysiology. Here, we developed an integrative approach to systematically identify and characterize non-coding regulatory variants with functional consequences

Epithelial plasticity - reversible modulation of a cell's epithelial and mesenchymal features - is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. While different master transcription factors and epigenetic modifiers have been implicated in this process in various contexts, the extent to which a unifying, generalized mechanism of transcriptional regulation

Although mutations in the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here we characterize 98 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3' splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most

A large international study found that the composition of the intestinal microbiome can predict clinical outcomes in patients undergoing allogenic hematopoietic-cell transplant (HCT) for blood cancers. The findings may help assess patients' transplantation-related mortality risk and aid in developing interventions to prevent or mitigate microbiome changes that affect HCT outcomes.

A chemotherapy-induced shift to ICOSL+ B cells in breast tumors correlated with better survival.

The pks + E. coli metabolite colibactin caused a unique mutational signature in intestinal organoids.

Symmetric division of stem cells positive for gastrin receptor CCK2R is linked to gastric cancer.