Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. Over the last years, several BET inhibitors have been developed and clinically tested. Results from the first clinical trials show limited single-agent activity in a small subset of patients with hematologic malignancies and in NUT carcinoma. Adverse events have been observed and may limit treatment compliance. Here, we review the preclinical rationale for targeting BET proteins in cancer and the preliminary results from clinical trials, and outline future directions for the use of BET inhibitors as antitumor agents. Significance: BET inhibitors represent a new class of anticancer agents. Results from the first clinical trials confirm the antitumor potential of BET inhibitors, but their efficacy as single agents seems to be limited. Based on preclinical data, combination therapies with other anticancer agents and the development of a new generation of compounds may open new possibilities for targeting BET proteins as effective anticancer strategies. Cancer Discov; 8(1); 24–36. ©2017 AACR.

The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4–NUT fusion oncoprotein. BRD4–NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types and is currently in clinical development. Antitumor activity was evaluated in four patients with advanced-stage NMC with confirmed BRD4–NUT fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate-use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of-concept evidence of clinical activity of a BRD inhibitor in targeting BRD4–NUT. Significance: We present the first clinical proof-of-concept that targeting BRD4–NUT with a BET inhibitor results in impressive and rapid antitumor activity in NMC. It offers strong potential for future clinical application in this rare patient population as either a single agent or in combination with other agents. Cancer Discov; 6(5); 492–500. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 461

Radiomics is an emerging field of research that aims to find associations between quantitative information extracted from imaging examinations and clinical data to support the best clinical decision. In the last few years, some papers have been evaluating the role of radiomics in gynecological malignancies, mainly focusing on ovarian cancer. Nonetheless, cervical cancer is the most frequent gynecological malignancy in developing countries and endometrial cancer is the most common in western countries. The purpose of this narrative review is to give an overview of the latest published papers evaluating the role of radiomics in cervical and endometrial cancer, mostly evaluating association with tumor prognostic factors, with response to therapy and with prediction of recurrence and distant metastasis.

Summary: Background CD37 is expressed on B-cell lymphoid malignancies, thus making it an attractive candidate for targeted therapy in non-Hodgkin lymphoma (NHL). IMGN529 is an antibody-drug conjugate comprising a CD37-binding antibody linked to the maytansinoid DM1, a potent anti-mitotic agent. Methods This first-in-human, phase 1 trial recruited adult patients with relapsed or refractory B-cell NHL. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity. IMGN529 was administered intravenously once every 3 weeks, and dosed using a conventional 3 + 3 dose-escalation design. Results Forty-nine patients were treated at doses escalating from 0.1 to 1.8 mg/kg. Dose limiting toxicities occurred in eight patients and included peripheral neuropathy, febrile neutropenia, neutropenia, and thrombocytopenia. The most frequent treatment-emergent adverse events were fatigue (39%), neutropenia, pyrexia, and thrombocytopenia (each 37%). Adverse events led to treatment discontinuation in 10 patients (20%). Eight patients (16%) had treatment-related serious adverse events, the most common being grade 3 febrile neutropenia. The MTD (with growth factor support) was 1.4 mg/kg every 3 weeks. IMGN529 plasma exposure increased monotonically with dose and was consistent with target-mediated drug disposition. Five (13%) of 39 response-evaluable patients achieved an objective response (one complete response and four partial responses), four of which occurred in the subgroup of patients with diffuse large B-cell lymphoma. Conclusions The manageable safety profile of IMGN529 and preliminary evidence of activity, particularly in DLBCL patients, support the continued development of this novel CD37-targeting agent.

Purpose: CB-103 selectively inhibits the CSL–NICD (Notch intracellular domain) interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This dose-escalation/expansion study aimed to determine safety, pharmacokinetics, and preliminary antitumor activity.Experimental Design: Patients ≥18 years of age with selected advanced solid tumors [namely, adenoid cystic carcinoma (ACC)] and hematologic malignancies were eligible. CB-103 was dosed orally in cycles of 28 days at escalating doses until disease progression. Notch-activating mutations were required in a dose confirmatory cohort. Endpoints included dose-limiting toxicities (DLT), safety, tumor response, pharmacokinetics, and pharmacodynamics. Exploratory analyses focused on correlates of Notch and target gene expression.Results: Seventy-nine patients (64, 12 dose-escalation cohorts; 15, confirmatory cohort) enrolled with 54% receiving two or more lines of prior therapy. ACC was the dominant tumor type (40, 51%). Two DLTs were observed [elevated gamma-glutamyl transferase (GGT), visual change]; recommended phase II dose was declared as 500 mg twice daily (5 days on, 2 days off weekly). Grade 3–4 treatment-related adverse events occurred in 15 patients (19%), including elevated liver function tests (LFTs), anemia, and visual changes. Five (6%) discontinued drug for toxicity; with no drug-related deaths. There were no objective responses, but 37 (49%) had stable disease; including 23 of 40 (58%) patients with ACC. In the ACC cohort, median progression-free survival was 2.5 months [95% confidence interval (CI), 1.5–3.7] and median overall survival was 18.4 months (95% CI, 6.3–not reached).Conclusions: CB-103 had a manageable safety profile and biological activity but limited clinical antitumor activity as monotherapy in this first-in-human study.Significance: CB-103 is a novel oral pan-Notch inhibitor that selectively blocks the CSL–NICD interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This first-in-human dose-escalation and -confirmation study aimed to determine the safety, pharmacokinetics, and preliminary antitumor efficacy of CB-103. We observed a favorable safety profile with good tolerability and biological activity but limited clinical single-agent antitumor activity. Some disease stabilization was observed among an aggressive NOTCH-mutant ACC type-I subgroup where prognosis is poor and therapies are critically needed. Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs.

The activation of the PI3K/AKT/mTOR pathway is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells, and, for this reason, represents an attractive target for developing targeted anti-cancer drugs. There are plenty of preclinical data sustaining the anti-tumor activity of dual PI3K/mTOR inhibitors as single agents and in combination in lymphomas. Clinical responses, including complete remissions (especially in follicular lymphoma patients), are also observed in the very few clinical studies performed in patients that are affected by relapsed/refractory lymphomas or chronic lymphocytic leukemia. In this review, we summarize the literature on dual PI3K/mTOR inhibitors focusing on the lymphoma setting, presenting both the three compounds still in clinical development and those with a clinical program stopped or put on hold.