A phase 1 study of IO-202, an anti-LILRB4 antibody, in chronic myelomonocytic leukemia and acute myeloid leukemia.

IO-202 is a humanized immunoglobulin G1 monoclonal antibody with high affinity and specificity for leukocyte immunoglobulin-like receptor B4 (LILRB4; ILT3), which is predominantly expressed in monocytes and monocytic blasts. IO-202 induces antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro and in patients with leukemia. Herein, we present the phase 1a dose escalation data of IO-202 as monotherapy and in combination with azacitidine (AZA) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and R/R chronic myelomonocytic leukemia (CMML), and the phase 1b dose expansion data of IO-202 combined with AZA for the treatment of hypomethylating agent (HMA)-naïve CMML.

Genetic and Cellular Architecture of Breast Cancer Risk in Multi-Ancestry Studies of 159,297 Cases and 212,102 Controls.

Breast cancer genome-wide association studies (GWAS) have identified over 200 independent genome-wide significant susceptibility markers. However, most studies have focused on one or two ancestral groups. We examined breast cancer genetic architecture using GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR) and Hispanic/Latina (H/L) samples, totaling 159,297 cases and 212,102 controls, comprising the largest multi-ancestry study of breast cancer to date.

Cancer of the ovary, fallopian tube, and peritoneum: 2025 update.

In 2014, FIGO's Committee for Gynecologic Oncology revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same system. Most of these malignancies are high-grade serous carcinomas (HGSCs). Stage IC is now divided into three categories: IC1 (surgical spill), IC2 (capsule ruptured before surgery or tumor on ovarian or fallopian tube surface), and IC3 (malignant cells in the ascites or peritoneal washings).

Talking with adolescent and young adult cancer survivors about health after cancer: A review and communication guide for clinicians.

Adolescent and young adult (AYA) cancer survivors represent a vulnerable population in cancer care and survivorship. AYA survivors are a heterogeneous group that includes people between the ages of 15 and 39 years who were treated for cancer during their childhood or AYA years, at which time they had variable agency and may have received cancer care in pediatric or adult settings. AYA survivors experience one or multiple health care transitions, moving from active oncology to posttreatment survivorship and/or from pediatric to adult care.

Development of Degraders and 2-pyridinecarboxyaldehyde (2-PCA) as a recruitment Ligand for FBXO22.

Targeted protein degradation (TPD) is a promising therapeutic strategy that requires the discovery of small molecules that induce proximity between E3 ubiquitin ligases and proteins of interest. FBXO22 is an E3 ligase that is overexpressed in many cancers and implicated in tumorigenesis. While FBXO22 was previously identified as capable of recognizing ligands bearing a primary amine degron, further investigation and development of recruitment ligands is required to enable its broader utility for TPD.

Brief Report: Prospective Trial of Pembrolizumab Monotherapy in Metastatic NSCLC Evaluating Circulating Tumor DNA as a Surrogate Biomarker of Response.

Immune checkpoint inhibitors provide clinical benefit to a subset of patients with metastatic NSCLC, yet the reliable prediction of long-term outcomes remains challenging. We conducted a prospective phase 2 clinical trial to evaluate circulating tumor DNA (ctDNA) as a surrogate biomarker for early clinical response to pembrolizumab monotherapy (NCT02955758). Tumor-informed targeted sequencing of pretreatment and early on-treatment plasma ctDNA in 25 patients with metastatic NSCLC was performed.

Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia.

Acute myeloid leukaemia (AML) remains a challenging haematological malignancy, with most patients developing resistance to standard-of-care (SOC) treatments. This resistance is often attributed to the overexpression of anti-apoptotic BCL-2 family proteins, which regulate the intrinsic apoptotic pathway by inhibiting pro-apoptotic effector proteins such as BAX and BAK. AML cells exploit this imbalance to evade apoptosis and sustain survival, necessitating the development of novel therapeutic strategies.

Pemigatinib for Myeloid/Lymphoid Neoplasms with Rearrangement.

Background: Myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 rearrangements (MLN-) are associated with poor prognosis. They are caused by chromosome 8p11 rearrangements that result in fusion genes and constitutive FGFR1 activation. We report on a phase 2 study, in which there were no concurrent control patients, termed FIGHT-203, in which we evaluated the FGFR1-3 inhibitor, pemigatinib, for the treatment of MLN-.

Clinical strategies for lung cancer management: Recommendations from the Bridging the Gaps Lung Cancer Consensus Conference 2024.

Clinical practice guidelines for nonsmall cell lung cancer (NSCLC) and small cell lung cancer include recommendations based on high-level clinical trial evidence, but complex clinical questions are frequently seen in real-world practice that are not clearly answered by prospective trial data. To address these questions, the Bridging the Gaps Lung Cancer Consensus Conference 2024 (BtG LCCC 2024) convened to develop US-focused expert guidance for clinical situations in which level 1 evidence is lacking. At BtG LCCC 2024, a multidisciplinary expert panel discussed ongoing clinical issues in small cell lung cancer management, targeted therapy in EGFR-mutated NSCLC, management of early stage NSCLC, identification and management of non-EGFR oncogene-driven NSCLC, and use of immunotherapy in advanced/metastatic NSCLC.

Whole exome sequencing identifies FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer in Hispanic/Latina women.

Breast cancer (BC) is one of the most common cancers globally. Genetic testing facilitates screening and informs targeted risk-reduction and treatments. However, genes included in testing panels are from European-ancestry studies.

Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation.

Glutarimide analogs, such as thalidomide, redirect the E3 ubiquitin ligase CRL4 to induce degradation of certain zinc finger (ZF) proteins. Although the core structural motif recognized by CRBN has been characterized, it does not fully explain substrate specificity. To explore the role of residues adjacent to this core motif, we constructed a comprehensive ZF reporter library of 9,097 reporters derived from 1,655 human ZF proteins and conducted a library-on-library screen with 29 glutarimide analogs to identify compounds that collectively degrade 38 ZF reporters.

Structural basis for the dynamic regulation of mTORC1 by amino acids.

The mechanistic target of rapamycin complex 1 (mTORC1) anchors a conserved signalling pathway that regulates growth in response to nutrient availability. Amino acids activate mTORC1 through the Rag GTPases, which are regulated by GATOR, a supercomplex consisting of GATOR1, KICSTOR and the nutrient-sensing hub GATOR2 (refs. ).

Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observe comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identifies distinct non-small cell lung cancer-like (NSCLC-like, KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles.

Self-Perceived Hearing Outcomes with Radiation and Cisplatin or Radiation and Cetuximab for Patients with HPV-Positive Oropharyngeal Cancer - Results from xxxxx.

Purpose: xxxx was a noninferiority phase 3 trial comparing the efficacy of radiation with either cisplatin (RT+Cis) or cetuximab (RT+Cetux) for patients with HPV+ oropharyngeal cancer (OPC). Perceived hearing handicap was included as a patient reported outcome (PRO) secondary endpoint. The primary hypothesis was that perceived hearing handicap would be greater for patients receiving RT+Cis compared to RT+Cetux.

Reproductive factors and risk of contralateral breast cancer by age and hormone receptor status: The California Breast Cancer Survivorship Consortium.

Associations between reproductive factors and the risk of developing a contralateral second primary invasive breast cancer (CBC) are inconclusive. A pooled cohort of women with a first primary invasive breast cancer (FBC) from five California-based studies (8045 stage I-III FBC diagnosed from 1994 to 2009) was linked with the California Cancer Registry; 532 CBC were identified. We analyzed harmonized data and evaluated associations with reproductive factors using Fine and Gray regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for study, age at FBC diagnosis, race and ethnicity, and other risk factors previously identified in this pooled dataset (hormone receptor status, first-degree family history of breast cancer).

SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics.

Background: The FDA approval of T cell receptor-engineered T cells (TCR-T) for synovial sarcoma demonstrates the potential for adoptive T cell therapies (ACTs) in solid tumors. However, the paucity of tumor-associated targets without expression in normal tissues remains a major bottleneck, especially in rare cancer subtypes.

Methods: We developed a comprehensive computational pipeline called SCAN-ACT that leverages single-cell RNA sequencing and multi-omics data from tumor and normal tissues to nominate and prioritize putative targets for both chimeric antigen receptor (CAR)- and TCR-T cells.

Adaptive cohort design and LAT1 expression scale: study protocol for a Phase 2a trial of QBS72S in breast cancer brain metastases.

Background: Breast cancer is the most common cause of cancer death among women and frequently metastasizes to the brain. Up to 30% of patients with breast-to-brain metastases will develop leptomeningeal disease (LMD), with poor survival, rapid neurologic decline, and no durable treatment options. The novel agent QBS72S, also known as QBS10072S, is designed to leverage the high expression of L-type amino acid transporter 1 (LAT1) on breast cancer cells and the blood-brain barrier.

Expanding the cytokine receptor alphabet reprograms T cells into diverse states.

T cells respond to cytokines through receptor dimers that have been selected over the course of evolution to activate canonical JAK-STAT signalling and gene expression programs. However, the potential combinatorial diversity of JAK-STAT receptor pairings can be expanded by exploring the untapped biology of alternative non-natural pairings. Here we exploited the common γ chain (γ) receptor as a shared signalling hub on T cells and enforced the expression of both natural and non-natural heterodimeric JAK-STAT receptor pairings using an orthogonal cytokine receptor platform to expand the γ signalling code.

Spontaneous and experimental models of lymph node metastasis.

Lymph node (LN) metastasis is a conserved feature across most solid organ malignancies and portends worse prognoses. Functionally, LN metastases induce systemic tumor-specific immune tolerance and may serve as a reservoir for distant metastases. Nonetheless, there are relatively few preclinical models for interrogating the biology of LN metastasis and its systemic effects at various stages of metastatic progression.

Remission Assessment by Circulating Tumor DNA in Large B-cell Lymphoma.

Purpose: Large B-cell lymphomas (LBCL) are curable, but patients with residual disease after therapy invariably experience progression. Ultrasensitive methods to detect circulating tumor DNA (ctDNA) as minimal measurable residual disease (MRD) may improve the determination of remission.

Methods: We integrated data from five prospective studies of frontline anthracycline-based chemotherapy in patients with LBCL.

EORTC/USCLC/ISCL consensus recommendations for management and treatment of cutaneous lymphoproliferative disorders.

Background: In recent classifications several cutaneous lymphomas were reclassified as lymphoproliferative disorder (LPD). These include primary cutaneous CD4-positive small/medium T-cell LPD (PCSM-TCLPD), primary cutaneous acral CD8+ T-cell LPD (acral CD8+ TLPD) and primary cutaneous marginal zone LPD (PCMZLPD; still classified as primary cutaneous marginal zone lymphoma (PCMZL) in the 5th edition of the WHO classification). The results of a survey among 30 cutaneous lymphoma centres on the effects of this new terminology on clinical management revealed considerable heterogeneity and emphasized the need to develop uniform recommendations for management and treatment of these disorders.

Controlling treatment toxicity in ovarian cancer to prime the patient for tumor extinction therapy.

High-grade serous ovarian cancer (HGSOC) remains a major clinical challenge. In particular among those patients with homologous recombination (HR)-proficient tumors (>50%), most eventually succumb to their disease due to high recurrence rates, acquired resistance, and cumulative toxicity. This report summarizes work from the 12 IMO Workshop in which we explored an alternative "extinction therapy" strategy for frontline treatment of HGSOC.

Investigating the role of neighborhood socioeconomic status and germline genetics on prostate cancer risk.

Genetic factors play an important role in prostate cancer (PCa) development with polygenic risk scores (PRS) predicting disease risk across genetic ancestries. However, there are few convincing modifiable factors for PCa and little is known about their potential interaction with genetic risk. Our study explores the role of neighborhood socioeconomic status (nSES)-and how it may interact with PRS-on PCa risk.