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Cyclin-dependent kinase (CDK) 4/6 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations
Conclusion: Combination therapy with CDK4/6 inhibitors and EGFR-TKIs may be a promising approach. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 15, 2023 Category: Drugs & Pharmacology Source Type: research

A phase Ib/II study of BLU-554, a fibroblast growth factor receptor 4 inhibitor in combination with CS1001, an anti-PD-L1, in patients with locally advanced or metastatic hepatocellular carcinoma
Conclusion: Preliminary data showed that BLU-554 in combination with CS1001 is safe and effective for treatment of patients with locally advanced or metastatic HCC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 10, 2023 Category: Drugs & Pharmacology Source Type: research

A Retrospective Review of Center for Biologics Evaluation and Research Advisory Committee Meetings in the Context of the FDA ’s Benefit-Risk Framework
AbstractThe US FDA Center for Biologics Evaluation and Research (CBER) is responsible for the regulation of biologically derived products. FDA has established Advisory Committees (AC) as vehicles to seek external expert advice on scientific and technical matters related to the development and evaluation of products regulated by the agency. We aimed to identify and evaluate common topics discussed in CBER AC meetings during the regulatory decision-making process for biological products and medical devices. We analyzed the content of 119 CBER-led AC meetings between 2009 and 2021 listed on the FDA AC webpage. We reviewed pub...
Source: The AAPS Journal - February 9, 2023 Category: Drugs & Pharmacology Source Type: research

Anti-cancer activity of ultra-short single-stranded polydeoxyribonucleotides
SummaryOne of the features that differentiate cancer cells is their increased proliferation rate, which creates an opportunity for general anti-tumor therapy directed against the elevated activity of replicative apparatus in tumor cells. Besides DNA synthesis, successful genome replication requires the reparation of the newly synthesized DNA. Malfunctions in reparation can cause fatal injuries in the genome and cell death. Recently we have found that the ultra-short single-stranded deoxyribose polynucleotides of random sequence (ssDNA) effectively inhibit the catalytic activity of DNA polymerase \(\beta\). This effect a...
Source: Investigational New Drugs - February 7, 2023 Category: Drugs & Pharmacology Source Type: research

Repurposed drug battles ‘brain-eating’ amoeba
In the summer of 2021, a 54-year-old man was brought to a hospital in Northern California after an unexplained seizure. When an MRI revealed a mysterious mass in the left side of his brain, he was transferred to the University of California, San Francisco (UCSF), Medical Center. A brain biopsy and other tests revealed not a tumor, but an incredibly rare infection of the central nervous system caused by the amoeba Balamuthia mandrillaris . One of several “brain-eating” amoebae that occasionally spark headlines, the pathogen kills more than 90% of people who contract it. But despite initial setbacks, the ...
Source: Science of Aging Knowledge Environment - February 3, 2023 Category: Geriatrics Source Type: research

A phase 1 open-label study to assess the relative bioavailability of TAK-931 tablets in reference to powder-in-capsule in patients with advanced solid tumors
SummaryIn this phase 1 open-label study, we assessed the relative bioavailability of a prototype tablet formulation of TAK-931, a cell division cycle 7 kinase inhibitor, in reference to the current powder-in-capsule (PIC) formulation in patients with advanced solid tumors for whom no effective standard treatment was available. Adult patients were randomized 1:1 in a crossover fashion to receive one dose of TAK-931 80 mg PIC on Day 1 and one dose of TAK-931 80 mg tablet on Day 3 (or the reverse sequence), followed by TAK-931 50 mg PIC once daily (QD) for 12 days starting from Day 5, before a 7-day rest period (Cycle 0)...
Source: Investigational New Drugs - February 1, 2023 Category: Drugs & Pharmacology Source Type: research

Toxicologic Pathology Forum: Opinion on Approaches for Reporting Toxic and Adverse Dose Levels in Nonclinical Toxicology Studies Supporting the Development of Anticancer Pharmaceuticals
Toxicol Pathol. 2023 Jan 25:1926233221146937. doi: 10.1177/01926233221146937. Online ahead of print.ABSTRACTThe advancement of an investigational new drug in humans is a significant developmental milestone. In first-in-human (FIH)-enabling toxicology studies, the highest dose without a test article-related adverse effect (no-observed-adverse-effect-level [NOAEL]) serves as the basis for deriving a safe FIH starting dose. For anticancer pharmaceuticals, the FIH dose may be calculated using the highest non-severely toxic dose (HNSTD) in nonrodent models or the dose severely toxic to 10% (STD10) in rodents. Given the practice...
Source: Toxicologic Pathology - January 25, 2023 Category: Pathology Authors: Renee R Hukkanen Tomoyuki Moriyama Daniel J Patrick Jonathan Werner Source Type: research

Novel pentacyclic derivatives and benzylidenes of the progesterone series cause anti-estrogenic and antiproliferative effects and induce apoptosis in breast cancer cells
AbstractThe promising antitumor effects of progesterone derivatives have been identified in many studies. However, the specific mechanism of action of this class of compounds has not been fully described. Therefore, in this study, we investigated the antiproliferative and (anti)estrogenic activities of novel pentacyclic derivatives and benzylidenes of the progesterone series. The antiproliferative effects of the compounds were evaluated on hormone-dependent MCF7 breast cancer cells using the MTT test. Estrogen receptor α (ERα) activity was assessed by a luciferase-based reporter assay. Immunoblotting was used to evaluat...
Source: Investigational New Drugs - January 25, 2023 Category: Drugs & Pharmacology Source Type: research

Viscosalactone B, a natural LSD1 inhibitor, inhibits proliferation in vitro and in vivo against prostate cancer cells
SummaryLysine-specific demethylase 1 (LSD1) has been a promising target to treat prostate cancer, and discovery of novel LSD1 inhibitors would have great clinical significance. In this work, viscosalactone B was first identified as a novel LSD1 inhibitor. Viscosalactone B isolated fromWithania Somnifera displayed antiproliferative activity against PC3, DU145, C42B, PC3/MDVR, DU145/MDVR, and C42B/MDVR cells with IC50 values of 1.17, 0.72, 3.86, 2.06, 0.96 and 1.15 μM, respectively. In comparison, it was a selective LSD1 inhibitor with an IC50 value of 970.27 nM and could induce a significant accumulation of LSD1 substr...
Source: Investigational New Drugs - January 24, 2023 Category: Drugs & Pharmacology Source Type: research

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study
Conclusion: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms inEGFR,ABCG2, andABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 13, 2023 Category: Drugs & Pharmacology Source Type: research