CNS Protective Effect of Selpercatinib in First-Line Fusion-Positive Advanced Non-Small Cell Lung Cancer.

JCO .Although the CNS activity of selpercatinib in patients with fusion-positive non-small cell lung cancer (NSCLC) has been previously described, the ability of potent RET inhibition to prevent new CNS metastases from developing has been challenging to measure without randomized data. Serial CNS scans were studied from LIBRETTO-431, a randomized phase III trial of selpercatinib versus platinum/pemetrexed ± pembrolizumab whose primary results have been previously disclosed.

Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer.

Purpose: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone.

Patients And Methods: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2).

Phase III study of selpercatinib versus chemotherapy ± pembrolizumab in untreated positive non-small-cell lung cancer.

Selpercatinib, a novel, highly selective and potent, inhibitor of , demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review.

LY2495655, an antimyostatin antibody, in pancreatic cancer: a randomized, phase 2 trial.

Background: Cachexia is a formidable clinical challenge in pancreatic cancer. We assessed LY2495655 (antimyostatin antibody) plus standard-of-care chemotherapy in pancreatic cancer using cachexia status as a stratifier.

Methods: In this randomized, phase 2 trial, patients with stage II-IV pancreatic cancer were randomized to 300 mg LY2495655, 100 mg LY2495655, or placebo, plus physician-choice chemotherapy from a prespecified list of standard-of-care regimens for first and later lines of care.

Myostatin Neutralization Results in Preservation of Muscle Mass and Strength in Preclinical Models of Tumor-Induced Muscle Wasting.

Skeletal muscle wasting occurs in a great majority of cancer patients with advanced disease and is associated with a poor prognosis and decreased survival. Myostatin functions as a negative regulator of skeletal muscle mass and has recently become a therapeutic target for reducing the loss of skeletal muscle and strength associated with clinical myopathies. We generated neutralizing antibodies to myostatin to test their potential use as therapeutic agents to attenuate the skeletal muscle wasting due to cancer.

Open-label, single-arm, phase II study of enzastaurin in patients with follicular lymphoma.

This open-label, phase II study investigated whether enzastaurin, a protein kinase C-beta (PKCβ) inhibitor, had activity in patients with grade 1 or 2 follicular lymphoma (FL). Adults with grade 1 or 2 FL who had no more than one prior treatment received oral enzastaurin continuously for up to 3 years. Of the 66 patients who received enzastaurin, 53 were evaluable for response.

Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders.

Purpose Of Review: This review summarizes recent progress in the development of myostatin inhibitors for the treatment of muscle wasting disorders. It also focuses on findings in myostatin biology that may have implications for the development of antimyostatin therapies.

Recent Findings: There has been progress in evaluating antimyostatin therapies in animal models of muscle wasting disorders.

A phase I study of pemetrexed in patients with relapsed or refractory acute leukemia.

Purpose: To investigate the toxicity profile, activity, pharmacokinetics, and pharmacodynamics of pemetrexed in leukemia.

Patients And Methods: Patients with refractory or relapsed acute leukemia were eligible. A phase I 3+3 design was implemented.

Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling.

Targeting protein kinase C (PKC) isoforms by the small molecule inhibitor enzastaurin has shown promising preclinical activity in a wide range of tumor cells. We further delineated its mechanism of action in multiple myeloma (MM) cells and found a novel role of beta-catenin in regulating growth and survival of tumor cells. Specifically, inhibition of PKC leads to rapid accumulation of beta-catenin by preventing the phosphorylation required for its proteasomal degradation.

Retrospective analysis of protein kinase C-beta (PKC-beta) expression in lymphoid malignancies and its association with survival in diffuse large B-cell lymphomas.

Background: Both mechanistic features and recent correlative findings suggest a potential role for protein kinase C-beta (PKC-beta) in tumor pathogenesis, particularly in B-cell malignancies. To evaluate the role of this gene in lymphoid malignancies, we analyzed global gene expression data to quantify PKC-beta expression across diagnostic groups and, when possible, determined correlations between PKC-beta expression and survival.

Results: Our analysis showed that the level of PKC-beta expression was highest in chronic lymphocytic leukemia and follicular lymphoma.

Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl).

In multiple myeloma (MM) protein kinase C (PKC) signaling pathways have been implicated in cell proliferation, survival, and migration. Here we investigated the novel, orally available PKC-inhibitor enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits phorbol ester-induced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCmu.

Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation.

In multiple myeloma (MM), migration is necessary for the homing of tumor cells to bone marrow (BM), for expansion within the BM microenvironment, and for egress into the peripheral blood. In the present study we characterize the role of vascular endothelial growth factor (VEGF) and beta(1) integrin (CD29) in MM cell migration. We show that protein kinase C (PKC) alpha is translocated to the plasma membrane and activated by adhesion of MM cells to fibronectin and VEGF.