The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS.

Recently reported to be effective in patients with lung cancer, KRAS inhibitors bind to the inactive, or guanosine diphosphate (GDP)–bound, state of the oncoprotein and require guanosine triphosphate (GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRAS hydrolyzes sufficient GTP to allow inactive state–selective inhibition.

The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML.

Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells.

Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer.

Background: Metastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.

Proton Therapy for Breast Cancer: A Consensus Statement From the Particle Therapy Cooperative Group Breast Cancer Subcommittee.

Radiation therapy plays an important role in the multidisciplinary management of breast cancer. Recent years have seen improvements in breast cancer survival and a greater appreciation of potential long-term morbidity associated with the dose and volume of irradiated organs. Proton therapy reduces the dose to nontarget structures while optimizing target coverage.

Atezolizumab, Bevacizumab, and Chemotherapy for Newly Diagnosed Stage III or IV Ovarian Cancer: Placebo-Controlled Randomized Phase III Trial (IMagyn050/GOG 3015/ENGOT-OV39).

Purpose: To evaluate the addition of the humanized monoclonal antiprogrammed death ligand-1 (PD-L1) antibody, atezolizumab, to platinum-based chemotherapy and bevacizumab in newly diagnosed stage III or IV ovarian cancer (OC).

Methods: This multicenter placebo-controlled double-blind randomized phase III trial (ClinicalTrials.gov identifier: NCT03038100) enrolled patients with newly diagnosed untreated International Federation of Gynecology and Obstetrics (FIGO) stage III or IV OC who either had undergone primary cytoreductive surgery with macroscopic residual disease or were planned to receive neoadjuvant chemotherapy and interval surgery.

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

Background: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker.

Methods: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer.

DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.

Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and pyroptosis. Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin. NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains, and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT).

Anti-ceramide single-chain variable fragment mitigates radiation GI syndrome mortality independent of DNA repair.

After 9/11, threat of nuclear attack on American urban centers prompted government agencies to develop medical radiation countermeasures to mitigate hematopoietic acute radiation syndrome (H-ARS) and higher-dose gastrointestinal acute radiation syndrome (GI-ARS) lethality. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS in preclinical models, no mitigator potentially deliverable under mass casualty conditions preserves GI tract. Here, we report generation of an anti-ceramide 6B5 single-chain variable fragment (scFv) and show that s.

Involved-Field Irradiation in Definitive Chemoradiotherapy for Locoregional Esophageal Squamous Cell Carcinoma: Results From the ESO-Shanghai 1 Trial.

Purpose: To evaluate the feasibility and efficacy of involved-field irradiation in definitive chemoradiation therapy for locoregional esophageal squamous cell carcinoma.

Methods And Materials: Patterns in recurrence and elective nodal failure were analyzed in patients from the previously published ESO-Shanghai 1 trial, who received definitive chemoradiation therapy with involved-field irradiation to 61.2 Gy in 34 fractions using intensity modulated radiation therapy planning.

The importance of multidisciplinary care for spine metastases: initial tumor management.

Spine metastases are very common in cancer patients often requiring urgent assessment and the initiation of therapy. Treatment paradigms have changed exponentially over the past decade with the evolution and integration of stereotactic body radiotherapy, minimally invasive spine techniques, and systemic options including biologics and checkpoint inhibitors. These advances necessitate multidisciplinary assessments and interventions to optimize outcomes.

Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.

Background: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.

Methods: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks.

Higher Checkpoint Inhibitor Arthritis Disease Activity may be Associated With Cancer Progression: Results From an Observational Registry.

Objective: To describe clinical features associated with cancer outcomes of patients with immune checkpoint inhibitor (ICI)-associated arthritis.

Methods: Observational study of patients with ICI-arthritis enrolled in a single-center registry. Arthritis phenotype and activity, medications, and cancer status were recorded at every visit.

KRAS Inhibition with Sotorasib in Advanced Solid Tumors.

Background: No therapies for targeting mutations in cancer have been approved. The p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers.

Association of Coffee Intake With Survival in Patients With Advanced or Metastatic Colorectal Cancer.

Importance: Several compounds found in coffee possess antioxidant, anti-inflammatory, and insulin-sensitizing effects, which may contribute to anticancer activity. Epidemiological studies have identified associations between increased coffee consumption and decreased recurrence and mortality of colorectal cancer. The association between coffee consumption and survival in patients with advanced or metastatic colorectal cancer is unknown.

Practice Recommendations for Lung Cancer Radiotherapy During the COVID-19 Pandemic: An ESTRO-ASTRO Consensus Statement.

Background: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic.

Methods: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process.

Senolytic CAR T cells reverse senescence-associated pathologies.

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells and has a beneficial role in wound-healing responses. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis.

Proton Reirradiation: Expert Recommendations for Reducing Toxicities and Offering New Chances of Cure in Patients With Challenging Recurrence Malignancies.

Local and regional recurrences are common following an initial course of radiotherapy, yet management of these recurrences remains a challenge. Reirradiation may be an optimal treatment approach for providing durable tumor control and even offering select patients with locoregional recurrences or new primary tumors a chance of cure, but photon reirradiation can be associated with considerable risks of high grade acute and late toxicities. The high conformality and lack of exit dose with proton therapy offer significant advantages for reirradiation.

Developmental Mutators and Early Onset Cancer.

A new hypothesis suggests that somatic genome remodeling during normal development can cause mutations that explain many early onset cancers in children and adults.

Why do young people get cancer?

Oncologists and cancer biologists are frequently confronted by the question of what causes cancer? This is particularly vexing for cancers affecting children and young adults who have had limited exposure to environmental mutagens and the effects of aging. Here, I focus on a general framework of the causes of early-onset cancer development in children and young adults by relating inherited and constitutional cancer predisposition, oncogenic pathogens, and developmental mutations. This framework has implications not only for mechanistic investigation of young cancers, but should also clarify improved strategies for their treatment, screening, and potential prevention.

Practice recommendations for lung cancer radiotherapy during the COVID-19 pandemic: An ESTRO-ASTRO consensus statement.

Background: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic.

Methods: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process.

Dissecting Anaplastic Thyroid Carcinoma: A Comprehensive Clinical, Histologic, Immunophenotypic, and Molecular Study of 360 Cases.

Anaplastic thyroid carcinoma (ATC) is nearly always fatal. Large studies on ATC are exceedingly rare. We aimed to study the clinical, genotypic, and histologic characteristics of ATC in the largest retrospective cohort of ATC to date.