<div>Abstract<p>Purpose: This global phase 1 trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective BCL-2 inhibitor, in patients with relapsed or refractory chronic or small lymphocytic leukemia (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase 2 dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%); fatigue (34.6%); nausea (30.8%); anemia and thrombocytopenia (28.8% each); neutropenia (26.9%); constipation (25.0%); vomiting (23.1%); headache (21.2%); peripheral edema and hypokalemia (17.3% each); and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%); thrombocytopenia (13.5%); and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response of 63.6% and median time to response of 2 (range, 2-8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.</p></div>
e23169 Background: Most cancers follow a polygenic mode of progression to ensure their survival; not defined by a single aberration but through multiple abnormalities acting in concert. Existing molecular profiling techniques are unable to account for this; thus, the clinical benefit derived has been marginal. Advances in parallel computing and machine learning algorithms may overcome limitations of current profiling tools. Here, we report on a novel predictive technology capable of constructing a digital avatar, based on collation of salient tumor cell genomic/cytogenetics as well as predicting drug sensitivity, which we validated experimentally in lymphoma cells for potential clinical translation. Methods: WES, cytogenetic and karyotype data from a patient-derived IgM-secreting B-lymphoplasmacytic lymphoma cell line (IgM-LPL, RPCI-WM1) was used in simulation/validation experiments. FDA approved and select experimental drugs (n~150) were simulated on the avatar. Validation studies measuring cell proliferation (MTS assay), apoptosis (Annexin-V staining), cell cycle and protein profiling (immunoblotting) were conducted. Results: Numerous aberrations including MYD88L265P mutation, absence of CXCR4 mutations and chromosomal abnormalities were configured in a predictive model. Several pathways were predicted as oncogenic drivers in the RPCI-WM1 avatar and drug screening simulations predicted for heightened lymphoma cell sensitivity towards tozasertib (AURK inhibitor), binimetinib (MEK inhibitor)- but resistance towards ribociclib (CDK4/6 inhibitor). These predictions were experimentally validated where RPCI-WM1 cells demonstrated an IC50 of ~10nM, ~100nM and > 1100nM towards tozasertib, binimetinib and ribociclib, respectively. Conclusions: Our preclinical proof of concept study in IgM-LPL cells demonstrates abilities of a novel technology to simulate prominent genomic features and resulting oncogenic pathways and predict sensitivity to therapeutic agents. In vitro validation and modeling studies show high correlation and prospective studies to validate this robust technology in a clinical setting are currently underway.
Abstract In a continuing search for curcuminoid (CUR) compounds with antitumor activity, a novel series of heterocyclic CUR–BF 2 adducts and CUR compounds based on indole, benzothiophene, and benzofuran along with their aryl pyrazoles were synthesized. Computational docking studies were performed to compare binding efficiency to target proteins involved in specific cancers, namely HER2, proteasome, VEGFR, BRAF, and Bcl‐2, versus known inhibitor drugs. The majority presented very good binding affinities, similar to, and even more favorable than those of known inhibitors. The indole‐based CUR–BF 2 and CUR compounds and their bis‐thiocyanato derivatives exhibited high anti‐proliferative and apoptotic activity by in vitro bioassays against a panel of 60 cancer cell lines, more specifically against multiple myeloma (MM) cell lines (KMS11, MM1.S, and RPMI‐8226) with significantly lower IC 50 values versus healthy PBMC cells; they also exhibited higher anti‐proliferative activity in human colorectal cancer cells (HCT116, HT29, DLD‐1, RKO, SW837, and Caco2) than the parent curcumin, while showing notably lower cytotoxicity in normal colon cells (CCD112CoN and CCD841CoN).
