Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers

Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03–6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.This study was supported by Janssen Research & Development, LLC.Peer reviewe

Safety and efficacy of the erdafitinib (erda) intravesical delivery system, TAR-210, in patients (pts) with non–muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) harboring select <i>FGFR</i> mutations or fusions: Phase 1 first-in-human study.

TPS583 Background: Treatment options are limited for pts with NMIBC and MIBC who experience disease recurrence or who are ineligible for or refuse standard of care. Erda, an oral selective pan-FGFR tyrosine kinase inhibitor, is approved in adults with locally advanced or metastatic urothelial cancer with select FGFR3/2 alterations ( alt) who have progressed during or after ≥1 line of platinum-containing chemotherapy. FGFRalt are among the most common oncogenic drivers detected in NMIBC and MIBC, and are more prevalent in NMIBC. TAR-210 is an intravesical drug delivery system designed to provide local, continuous release of erda within the bladder, thus limiting systemic toxicity. This study evaluates the safety, pharmacokinetics (PK), and efficacy of TAR-210 in pts with NMIBC or MIBC with select FGFRalt. Methods: Open-label, multicenter phase 1 study of TAR-210 in pts with recurrent NMIBC or MIBC (NCT05316155). Eligible pts are aged ≥18 yrs with adequate organ function and tumors with select FGFRalt. A flexible molecular eligibility strategy is used to allow for local or central fresh/archival tissue-based FGFR testing by next-generation sequencing (NGS) or PCR, or urine cell-free DNA NGS testing. Four cohorts will be enrolled: pts with recurrent, bacillus Calmette-Guerin (BCG)-experienced papillary-only high-risk (HR) NMIBC (high-grade Ta/T1) refusing or ineligible for radical cystectomy (RC) (Cohort 1) or scheduled for RC (Cohort 2); pts with recurrent, intermediate-risk NMIBC (Ta/T1) with a history of low-grade disease (Cohort 3); pts with cT2-T3a MIBC scheduled for RC refusing or ineligible for neoadjuvant cisplatin (Cohort 4). Pts in Cohorts 1 and 2 will have TURBT with resection of all visible disease prior to dosing, whereas pts in Cohort 3 must have visible disease prior to dosing. The primary end point is safety (adverse events, including dose-limiting toxicity). Secondary end points include PK, recurrence-free survival (Cohorts 1 and 2), complete response (CR) rate and duration of CR (Cohort 3), and pathologic CR rate, pT0 rate, and rate of downstaging to &lt;pT2 (Cohort 4). Dose escalation (Part 1; n≈12, Cohorts 1 and 3 only) will be followed by dose expansion (Part 2; n≈50-80). Cohorts 1 and 3: response assessment will be after a 3-mo dosing cycle; pts with CR may receive ≤3 additional 3-mo dosing cycles if no recurrence, progression, or unacceptable toxicity. Cohorts 2 and 4: response assessment will be at RC after 8 wks of dosing. Follow-up disease surveillance (cystoscopy, urine cytology, imaging) will be every 3 mos to end of Yr 2 and every 6 mos in Yr 3 in Cohorts 1 and 3 and at 3 mos post-RC in Cohorts 2 and 4. Four pts were enrolled since April 2022 (1 in Cohort 1, 3 in Cohort 3); enrollment for Cohorts 2 and 4 is planned soon. Clinical trial information: NCT05316155 . </jats:p

TMSB4Y is a candidate tumor suppressor on the Y chromosome and is deleted in male breast cancer

Male breast cancer comprises less than 1% of breast cancer diagnoses. Although estrogen exposure has been causally linked to the development of female breast cancers, the etiology of male breast cancer is unclear. Here, we show via fluorescence in situ hybridization (FISH) and droplet digital PCR (ddPCR) that the Y chromosome was clonally lost at a frequency of ~16% (5/31) in two independent cohorts of male breast cancer patients. We also show somatic loss of the Y chromosome gene TMSB4Y in a male breast tumor, confirming prior reports of loss at this locus in male breast cancers. To further understand the function of TMSB4Y, we created inducible cell lines of TMSB4Y in the female human breast epithelial cell line MCF-10A. Expression of TMSB4Y resulted in aberrant cellular morphology and reduced cell proliferation, with a corresponding reduction in the fraction of metaphase cells. We further show that TMSB4Y interacts directly with Β-actin, the main component of the actin cytoskeleton and a cell cycle modulator. Taken together, our results suggest that clonal loss of the Y chromosome may contribute to male breast carcinogenesis, and that the TMSB4Y gene has tumor suppressor properties

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Patients with Lower-Risk Myelodysplastic Syndromes

Abstract Background Myelodysplastic syndromes (MDS) are characterized by frequent mutations in RNA splicing factor genes. Protein arginine methyltransferase 5 (PRMT5) regulates the activity of the splicing machinery through methylation of key spliceosome proteins. PRMT5 inhibitors have demonstrated preferential killing of acute myeloid leukemia cells with splicing factor mutations. JNJ-64619178 is a potent, selective, oral PRMT5 inhibitor that causes accumulation of splicing abnormalities in preclinical models. It is hypothesized that inhibition of PRMT5 by JNJ-64619178 may target splicing factor gene mutant MDS clones, leading to recovery of normal hematopoiesis. Here we present Part 2 of a phase 1 study of JNJ-64619178 evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of JNJ-64619178 in adult patients (pts) with lower risk MDS (International Prognostic Scoring System [IPSS] score Low or Intermediate-1) who are red blood cell (RBC) transfusion-dependent and relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment. Methods Dosing was initiated at 2 mg, 14 days on/7 days off (intermittent) on a 21-day cycle, a tolerable dose from the ongoing dose escalation in solid tumors and lymphomas in Part 1. Confirmation of tolerability followed a modified 3+3 design with de-escalation allowed based on the totality of the data. Enrollment was expanded at the selected, tolerable dose level to further evaluate safety, PK, PD, and preliminary clinical activity. Results As of 29 May 2021, 21 pts were enrolled. Median age was 71 (range 52-85). Revised IPSS score was Very Low (10%), Low (71%) or Intermediate (19%). Pts had a median of 1 prior line of therapy post-ESA (range 0-4), including lenalidomide (33%), hypomethylating agents (29%), and luspatercept (19%). SF3B1 mutations were identified in 71% of pts. Median treatment duration was 3.1 months (range 0.03-6.37). No dose-limiting toxicities were observed. While the 2 mg intermittent starting dose was tolerable, lower dose schedules of 1 mg intermittent and 0.5 mg continuous (once daily [QD]) dosing were evaluated to reduce myelosuppression, and enrollment was expanded at 0.5 mg QD (n=13 pts). Fifteen pts (71%) experienced ≥1 treatment emergent adverse event (TEAE) that was considered related to the study agent (TRAE). TRAE in &amp;gt;10% of pts were thrombocytopenia (52%), neutropenia (48%), anemia (19%), and dysgeusia (14%). Grade 3 or higher TRAE were reported for 57% of pts. Grade 3 or higher TRAE worsening from baseline in &amp;gt;1 pt were neutropenia (29%); anemia and thrombocytopenia (19.0% each); and diarrhea (9%). TEAEs contributed to treatment interruption, dose reduction, and treatment discontinuation in 57%, 14%, and 19% of pts, respectively. Anemia, thrombocytopenia, and neutropenia were the only TRAE leading to treatment modification in &amp;gt;1 pt. Hematologic toxicities were dose-dependent and reversible. Grade ≥3 thrombocytopenia and neutropenia were observed, respectively, in 67% and 50% of pts at 2 mg intermittent versus 0% and 31% at 0.5 mg QD. Serious AE considered possibly related to JNJ-64619178 by the investigator included 1 pt with Grade 3 anemia and 1 pt with Grade 1 atrial fibrillation, Grade 3 cardiac troponin I increase, and Grade 5 cardiac failure (&amp;gt;30 days from last dose). One other death of unknown cause was not considered related to treatment. Comparison of the multiple dose C trough across all dose levels suggests a dose-dependent increase in JNJ-64619178 plasma concentration. Robust target engagement, as measured by plasma symmetric dimethylarginine, was achieved at all dose levels. Serial analysis of variant allele frequency of clonal mutations in a subset of pts did not show significant reductions from baseline in peripheral blood or bone marrow. No pts experienced objective response or hematologic improvement according to International Working Group criteria, RBC transfusion independence, or meaningful reduction in transfusion requirements. Conclusion JNJ-64619178 demonstrated primarily hematologic toxicity in pts with transfusion-dependent lower-risk MDS, which was manageable at the selected expansion dose. Despite robust target engagement, clinical activity was not observed, and enrollment was stopped. The role of PRMT5 in MDS and the differential impact of PRMT5 inhibition on normal and malignant hematopoiesis require further study. Disclosures Platzbecker: Novartis: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria. Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Brunner: Agios: Consultancy; Keros Therapeutics: Consultancy; Aprea: Research Funding; AstraZeneca: Research Funding; GSK: Research Funding; Acceleron: Consultancy; Janssen: Research Funding; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Morillo: Janssen: Honoraria; Abbvie: Honoraria; Takeda: Honoraria. Patel: Acerta Pharma: Research Funding; Curis: Research Funding; Clovis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aileron Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Effector Therapeutics: Research Funding; Eli Lilly: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Evelo Biosciences: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jounce Therapeutics: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Loxo Oncology: Research Funding; LSK Biopartners: Research Funding; Lycera: Research Funding; Mabspace: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Millennium Pharmaceuticals: Research Funding; Mirati Therapeutics: Research Funding; ModernaTX: Research Funding; ORIC Pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Phoenix Molecular Designs: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Stemline Therapeutics: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Tesaro: Research Funding; TopAlliance: Research Funding; Vedanta: Research Funding; Verastem: Research Funding; Vigeo: Research Funding; Xencor: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Daiichi Sankyo: Research Funding; Cyteir Therapeutics: Research Funding; Ciclomed: Research Funding; Checkpoint Therapeutics: Research Funding; Calithera: Research Funding; Boehringer Ingelheim: Research Funding; Bicycle Therapeutics: Research Funding; AstraZeneca: Research Funding; Artios Pharma: Research Funding; Agenus: Research Funding; Florida Cancer Specialists: Research Funding; BioNTech: Research Funding; Incyte: Research Funding; Forma Therapeutics: Research Funding; Ignyta: Research Funding; Hutchinson MediPharma: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Hengrui: Research Funding; H3 Biomedicine: Research Funding; GlaxoSmithKline: Research Funding. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures; Takeda: Consultancy. Lauring: Janssen Research and Development: Current Employment; Johnson and Johnson: Current holder of stock options in a privately-held company. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company. </jats:sec

PIK3CA mutations and EGFR overexpression predict for lithium sensitivity in human breast epithelial cells

A high frequency of somatic mutations has been found in breast cancers within the gene encoding the catalytic p110α subunit of PI3K, PIK3CA. Using isogenic human breast epithelial cells, we have previously demonstrated that oncogenic PIK3CA “hotspot” mutations predict for response to the toxic effects of lithium. However, other somatic genetic alterations occur within this pathway in breast cancers, and it is possible that these changes may also predict for lithium sensitivity. We overexpressed the epidermal growth factor receptor (EGFR) into the non-tumorigenic human breast epithelial cell line MCF-10A, and compared these cells to isogenic cell lines previously created via somatic cell gene targeting to model Pten loss, PIK3CA mutations, and the invariant AKT1 mutation, E17K. EGFR overexpressing clones were capable of cellular proliferation in the absence of EGF and were sensitive to lithium similar to the results previously seen with cells harboring PIK3CA mutations. In contrast, AKT1 E17K cells and PTEN−/− cells displayed resistance or partial sensitivity to lithium, respectively. Western blot analysis demonstrated that lithium sensitivity correlated with significant decreases in both PI3K and MAPK signaling that were observed only in EGFR overexpressing and mutant PIK3CA cell lines. These studies demonstrate that EGFR overexpression and PIK3CA mutations are predictors of response to lithium, whereas Pten loss and AKT1 E17K mutations do not predict for lithium sensitivity. Our findings may have important implications for the use of these genetic lesions in breast cancer patients as predictive markers of response to emerging PI3K pathway inhibitors