Regulation of skeletal muscle oxidative capacity and insulin signaling by the Mitochondrial Rhomboid Protease PARL

Type 2 diabetes mellitus (T2DM) and aging are characterized by insulin resistance and impaired mitochondrial energetics. In lower organisms, remodeling by the protease pcp1 (PARL ortholog) maintains the function and lifecycle of mitochondria. We examined whether variation in PARL protein content is associated with mitochondrial abnormalities and insulin resistance. PARL mRNA and mitochondrial mass were both reduced in elderly subjects and in subjects with T2DM. Muscle knockdown of PARL in mice resulted in malformed mitochondrial cristae, lower mitochondrial content, decreased PGC1&alpha; protein levels, and impaired insulin signaling. Suppression of PARL protein in healthy myotubes lowered mitochondrial mass and insulin-stimulated glycogen synthesis and increased reactive oxygen species production. We propose that lower PARL expression may contribute to the mitochondrial abnormalities seen in aging and T2DM.<br /

Identification of a Rare Coding Variant in Complement 3 Associated with Age-related Macular Degeneration

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry matched controls revealed two large-effect rare variants; previously described R1210C in the CFH gene (fcase = 0.51%, fcontrol = 0.02%, OR = 23.11), and newly identified K155Q in the C3 gene (fcase = 1.06%, fcontrol = 0.39%, OR = 2.68). The variants suggest decreased inhibition of C3 by Factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology

Phase I study of the mutant IDH1 inhibitor ivosidenib: Long-term safety and clinical activity in patients with conventional chondrosarcoma

11532 Background: Chondrosarcomas (CS) are rare primary bone malignancies for which there are no approved systemic therapies. 85% of CS are the conventional subtype. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in ~50% of conventional CS. In a phase 1 study in patients (pts) with IDH1-mutated advanced solid tumors, ivosidenib (IVO), an oral potent inhibitor of mutant IDH1, demonstrated manageable toxicity (without dose-limiting toxicities), suppression of the oncometabolite 2-hydroxyglutarate at dose levels ≥300 mg/day, and disease control in pts with conventional CS. We report long-term safety, tolerability and efficacy of IVO in pts with conventional CS. Methods: In this phase I multicenter open-label dose-escalation and expansion study, IVO was administered orally (100 mg twice/day [BID] to 1200 mg once/day [QD]) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcomes included clinical activity (objective response rates [ORR, defined as complete response (CR) + partial response (PR)], stable disease [SD] and progression-free survival [PFS]). Adverse events (AEs) were assessed every visit and reported per the Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: 13 pts with advanced conventional CS were included in this analysis (data cut off 15 September 2022; women, n = 4; median age 54.0; AJCC tumor grade I [n = 2], II [n = 8], III [n = 1], unknown [n = 2]; 6 had received prior systemic therapy; received 100 mg IVO BID [n = 1], 400 mg QD [n = 1], 500 mg QD [n = 7], 800 mg QD [n = 2], and 1200 mg QD [n = 2]). Median treatment duration was 11.3 months (range: 0.5-92.6 months). Four pts (30.8%) have continued therapy for > 6 years (two of which were treated for > 7 years). Median relative dose intensity was 100%. The most frequent treatment emergent AEs (in > 4 pts; mostly grade 1/2) were diarrhea (n = 5) and nausea (n = 5). Six pts experienced grade ≥3 AEs. Three pts experienced serious AEs (none considered related to treatment). There were no discontinuations, dose reductions or deaths due to AEs. The ORR was 23.1%. Median duration of response was 42.5 months (range: 25.8-51.8 months). One pt with a base of the skull lesion achieved a CR (1200 mg IVO QD); two achieved PR (one 500 mg and one 1200 mg IVO QD); seven had SD (five received ≥500 mg IVO QD) and two had PD (both received ≥500 mg IVO QD). All responses occurred after > 2 years on treatment. Median PFS was 7.4 months (95% CI: 2.0-61.3). Conclusions: In pts with IDH1 mutated advanced conventional CS, IVO demonstrates manageable toxicity and durable disease control including long-term responses, extending several years for a proportion of pts. Future studies are warranted to better understand the efficacy of IVO in pts with advanced conventional CS. Clinical trial information: NCT02073994

Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials

Abstract Background Immunotherapies, specifically those based on immune checkpoint inhibitors, have shown promising activity in multiple tumor types. Other than mifamurtide (MEPACT®) for osteosarcoma approved by European Medicines Agency, there are no approved immunotherapies for sarcomas. Methods We analyzed medical records of patients with advanced sarcoma who were referred to Phase 1 clinic at MD Anderson and received an immunotherapy (checkpoint inhibitors, vaccines, or cytokine based therapies). Clinical parameters including demographics, clinical history, toxicity, and response were abstracted. Results Among 50 patients enrolled in immunotherapy trials (Bone 10; Soft-tissue 40) we found 14 different subtypes of sarcomas. Royal Marsden Hospital (RMH) prognostic score was <2 (86%). Performance status (PS) was 0–1 in 48 patients (96%); median number of prior therapies was 3 (0–12). Immunotherapy consisted of checkpoint inhibitors (82%: PD1 = 7, PD-L1 = 11, CTLA4 = 22, other = 1) of which 42% were combinations, as well as vaccines (14%), and cytokines (4%). Median overall survival (OS) was 13.4 months (11.2 months: not reached). Median progression free survival (PFS) was 2.4 months (95% CI = 1.9–3.2 months). Best response was partial response (PR) in 2 patients with alveolar soft part sarcoma (ASPS) and stable disease (SD) in 11 patients (3 GIST, 3 liposarcomas (2 DDLS, 1 WDLS), 2 ASPS, 2 leiomyo, 1 osteo). PFS was 34% (23%, at 50%) at 3 months, 16% (8%, 30%) at 6 months, and 6% (2%, 20%) at 1 year. Pseudo-progression followed by stable disease was observed in 2 patients (4%). Grade 3/4 adverse events included rash (10%), fever (6%), fatigue (6%), and nausea/vomiting (6%). Conclusion Immunotherapies were well tolerated in advanced sarcoma patients enrolled in trials. All four ASPS patients had clinical benefit with checkpoint inhibitors and this was the only subtype experiencing partial response. Further evaluation of checkpoint inhibitors in ASPS is warranted