Selected Articles from This Issue

Advanced breast cancers associated with germline breast cancer susceptibility gene (gBRCA) mutations are sensitive to platinum chemotherap. and poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi). However, shared mechanisms of acquired resistance to these therapies may exist, including BRCA reversion mutations. Puhalla and colleagues report on outcomes and biomarker assessment among patients with advanced HER2-negative gBRCA-associated breast cancer enrolled in the BROCADE3 phase III trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel. Crossover veliparib monotherapy demonstrated limited antitumor activity in patients who experienced disease progression on placebo plus carboplatin/paclitaxel. Platinum-free interval appeared to affect veliparib activity. Thus, BRCA reversion mutations may promote cross-resistance and limit veliparib activity following progression on platinum.

Glutamine is a critical fuel for solid tumors, and interference with glutamine metabolism is deleterious to neoplasia in preclinical models. Harding and colleagues describe the results of a phase I dose escalation trial of the oral, first-in-class, glutaminase inhibitor telaglenastat, conducted in treatment-refractory solid tumor patients. Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Disease control rate was 43% across expansion cohorts with an objective response in a patient with renal cell carcinoma. Telaglenastat is tolerable with a favorable PK/PD profile and able to achieve the desired inhibition of glutaminase to support further clinical development.

Minimal residual disease (MRD) has become an important parameter in assessing the disease burden in multiple myeloma (MM) patients. Currently, the assays used to measure MRD require invasive bone marrow aspiration, which prevents frequent sampling. M-protein is a well-established biomarker used for MM monitoring. In this study, Liyasova and colleagues demonstrate that residual levels of M-protein can be accurately and sensitively monitored in serial serum samples by mass spectrometry. The new assay, called EasyM, was shown to be a noninvasive, sensitive assay that can be performed frequently to monitor the disease status in CR patients and was able to predict relapse earlier than conventional testing with superior performance making it ideal for MM monitoring and relapse prediction.

Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL) is a common high-risk leukemia subtype associated with hyperactive kinase signaling and poor clinical outcomes. To identify synergistic codependencies in Ph-like ALL for combinatorial targeted therapies, Ding and colleagues performed unbiased network analysis of large-scale patient genomic and transcriptomic datasets. They identified 14 key genetic regulators in Ph-like ALL and demonstrated synergistic efficacy of cotargeting the pair of top-ranked regulators BCL-2 and STAT5 with venetoclax and ruxolitinib or dasatinib, respectively, in vitro and in vivo in preclinical Ph-like ALL models. This systems biology approach to combination target discovery is important given the high rates of chemoresistance and relapse in patients with Ph-like ALL and may be broadly applicable to other cancer types.