The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.

Several therapeutic agents have been approved for treating multiple myeloma (MM), a cancer of bone marrow resident plasma cells. Predictive biomarkers for drug response could help guide clinical strategies to optimize outcomes. Here, we present an integrated functional genomic analysis of tumor samples from MM patients that were assessed for their ex vivo drug sensitivity to 37 drugs, clinical variables, cytogenetics, mutational profiles, and transcriptomes.

Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties.

The UNC-51-like kinase-1 (ULK1) is one of the central upstream regulators of the autophagy pathway, represents a key target for the development of molecular probes to abrogate autophagy and explore potential therapeutic avenues. Here we report the discovery, structure-activity and structure-property relationships of selective, potent, and cell-active ULK1/2 inhibitors based on a 7-azaindole scaffold. Using structure-based drug design, we have developed a series of analogs with excellent binding affinity and biochemical activity against ULK1/2 (IC < 25 nM).

A phase I/IB trial of binimetinib in combination with erlotinib in NSCLC harboring activating KRAS or EGFR mutations.

Background: Activating mutations in EGFR or KRAS are highly prevalent in NSCLC, share activation of the MAPK pathway and may be amenable to combination therapy to prevent negative feedback activation.

Methods: In this phase 1/1B trial, we tested the combination of binimetinib and erlotinib in patients with advanced NSCLC with at least 1 prior line of treatment (unless with activating EGFR mutation which could be treatment-naïve). A subsequent phase 1B expansion accrued patients with either EGFR- or KRAS-mutation using the recommended phase 2 dose (RP2D) from Phase 1.

A phase I trial of metformin in combination with vincristine, irinotecan, and temozolomide in children with relapsed or refractory solid and central nervous system tumors: A report from the national pediatric cancer foundation.

Background: Patients with relapsed and refractory solid and central nervous system (CNS) tumors have poor outcomes and need novel therapeutic options. Vincristine, irinotecan, and temozolomide (VIT) is a common chemotherapy regimen in relapsed pediatric tumors with an established toxicity profile. Metformin shows preclinical anti-cancer activity through multiple pathways.

Targeting Casein Kinase 1 Delta Sensitizes Pancreatic and Bladder Cancer Cells to Gemcitabine Treatment by Upregulating Deoxycytidine Kinase.

Although gemcitabine is the cornerstone of care for pancreatic ductal adenocarcinoma (PDA), patients lack durable responses and relapse is inevitable. While the underlying mechanisms leading to gemcitabine resistance are likely to be multifactorial, there is a strong association between activating gemcitabine metabolism pathways and clinical outcome. This study evaluated casein kinase 1 delta (CK1δ) as a potential therapeutic target for PDA and bladder cancer, in which CK1δ is frequently overexpressed.

Preclinical testing of 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide: a potent protein kinase C-ι inhibitor as a potential prostate carcinoma therapeutic.

Protein kinase C-iota (PKC-ι) is an oncogene overexpressed in many cancer cells including prostate, breast, ovarian, melanoma, and glioma. Previous in-vitro studies have shown that 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1s), a PKC-ι specific inhibitor, is effective against some cancer cell lines by decreasing cell growth and inducing apoptosis. To assess ICA-1s as a possible therapeutic, in-vivo studies using a murine model were performed.

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth.

Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor- or host-derived MMP-2 contributes to breast cancer growth and does so by processing substrates, including type I collagen and TGFβ latency proteins.