Search

The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and anti-apoptotic signaling in various lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are typically partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing a variety of lymphoid malignancies. OSI-027, but not rapamycin, inhibited phosphorylation of Akt at Ser473, a direct target of mTORC2, in multiple lymphoid lines. In further contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027-induced apoptosis depended upon transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027-induced apoptosis in vitro. Consistent with these results, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, upregulated Puma, and induced regressions in Jeko xenografts, derived from a patient with mantle cell lymphoma. Collectively, these studies not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo. [ABSTRACT FROM AUTHOR]

Purpose of review: BRCA1 and BRCA2 mutation carriers can be at increased cardiovascular risk. The goal of this review is to provide information about factors associated with increased cardiovascular risk, methods to prevent cardiovascular toxicities, and recommended screening guidelines.Recent findings: BRCA1/2 mutation carriers who are diagnosed with cancer are often exposed to chemotherapy, chest radiotherapy, and/or HER2 directed therapies, all of which can be cardiotoxic. In addition, BRCA1/2 carriers often undergo prophylactic salpingoopherectomies, which may also increase cardiovascular risks.Summary: Understanding the potential for increased cardiovascular risk in individuals with a BRCA1 or BRCA2 mutation, as well as gold standard practices for prevention, detection, and treatment of cardiac concerns in this population, is important. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR), a kinase that regulates proliferation and apoptosis, has been extensively evaluated as a therapeutic target in multiple malignancies. Rapamycin analogs, which partially inhibit mTOR complex 1 (mTORC1), exhibit immunosuppressive and limited antitumor activity, but sometimes activate survival pathways through feedback mechanisms involving mTORC2. Thus, attention has turned to agents targeting bothmTORcomplexes by binding themTORactive site. Herewe show that disruption of eithermTOR-containingcomplex is toxic to acutelymphocytic leukemia (ALL) cells and identify 2 previously unrecognized pathways leading to this cell death. Inhibition of mTORC1-mediated 4EBP1 phosphorylation leads to decreased expression of c-MYC and subsequent upregulation of the proapoptotic BCL2 family member PUMA, whereas inhibition of mTORC2 results in nuclear factor-κB–mediated expression of the Early Growth Response 1 (EGR1) gene, which encodes a transcription factor that binds and transactivates the proapoptotic BCL2L11 locus encoding BIM. Importantly, 1 or both pathways contribute to death of malignant lymphoid cells after treatment with dual mTORC1/mTORC2 inhibitors. Collectively, these observations not only provide new insight into the survival roles of mTOR in lymphoid malignancies, but also identify alterations that potentially modulate the action of mTOR dual inhibitors in ALL. [ABSTRACT FROM AUTHOR]

Background: Cancer distress management is an evidence-based component of comprehensive cancer care. Group-delivered cognitive behavioral therapy for cancer distress (CBT-C) is the first distress treatment associated with replicated survival advantages in randomized clinical trials. Despite research supporting patient satisfaction, improved outcomes, and reduced costs, CBT-C has not been tested sufficiently within billable clinical settings, profoundly reducing patient access to best-evidence care. This study aimed to adapt and implement manualized CBT-C as a billable clinical service., Patients and Methods: A stakeholder-engaged, mixed-methods, hybrid implementation study design was used, and the study was conducted in 3 phases: (1) stakeholder engagement and adaptation of CBT-C delivery, (2) patient and therapist user testing and adaptation of CBT-C content, and (3) implementation of practice-adapted CBT-C as a billable clinical service focused on evaluation of reach, acceptability, and feasibility across stakeholder perspectives., Results: A total of 40 individuals and 7 interdisciplinary group stakeholders collectively identified 7 primary barriers (eg, number of sessions, workflow concerns, patient geographic distance from center) and 9 facilitators (eg, favorable financial model, emergence of oncology champions). CBT-C adaptations made before implementation included expanding eligibility criteria beyond breast cancer, reducing number of sessions to 5 (10 total hours), eliminating and adding content, and revising language and images. During implementation, 252 patients were eligible; 100 (40%) enrolled in CBT-C (99% covered by insurance). The primary reason for declining enrollment was geographic distance. Of enrollees, 60 (60%) consented to research participation (75% women; 92% white). All research participants completed at least 60% of content (6 of 10 hours), with 98% reporting they would recommend CBT-C to family and friends., Conclusions: CBT-C implementation as a billable clinical service was acceptable and feasible across cancer care stakeholder measures. Future research is needed to replicate acceptability and feasibility results in more diverse patient groups, test effectiveness in clinical settings, and reduce barriers to access via remote delivery platforms.

Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1-3, 8-10, and 15-17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1-3, 8-10, and 15-17 along with topotecan 3 mg/m 2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1-26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2 , or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation. Clin Cancer Res; 24(4); 744-52. ©2017 AACR ., (©2017 American Association for Cancer Research.)