Quantitation of the DNA-dependent protein kinase inhibitor peposertib (M3814) and metabolite in human plasma by LC-MS/MS.

The DNA-dependent protein kinase (DNA-PK) is an abundant nuclear protein that mediates DNA double-strand break repair by nonhomologous end joining (NHEJ). As such, DNA-PK is critical for V(D)J recombination in lymphocytes and for survival in cells exposed to ionizing radiation and clastogens. Peposertib (M3814) is a small molecule DNA-PK inhibitor currently in preclinical and clinical development for cancer treatment.

Quantitation of tazemetostat in human plasma using liquid chromatography-tandem mass spectrometry.

To support a phase 1 trial in patients with lymphomas, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for tazemetostat quantitation in 20 μL of human plasma. After protein precipitation, chromatographic separation employed a Kinetex C18 column and a gradient of 0.1% formic acid in both water and acetonitrile, during a 3-min run time.

An LC-MS/MS method for determination of the bromodomain inhibitor ZEN-3694 and its metabolite ZEN-3791 in human plasma.

We have developed and validated a novel LC-MS/MS method for the simultaneous quantification of ZEN-3694 and its active metabolite ZEN-3791 in human plasma after protein precipitation. Stable isotope-labeled versions were used as internal standards. Chromatographic separation was achieved on a Kinetex C18 column using 0.

Randomized placebo-controlled, double-blind clinical trial of nanoemulsion curcumin in women with aromatase inhibitor-induced arthropathy: an Alliance/NCORP pilot trial.

Purpose: Aromatase inhibitor (AI) therapy reduces risk of recurrence and death for postmenopausal women with breast cancer (BC); however, AI-induced arthralgia (AIIA) can lead to discontinuation of treatment. Curcumin, a bioactive polyphenolic substance, may help ameliorate inflammation-related conditions including osteoarthritis and pain.

Methods: We conducted a multisite randomized placebo-controlled, double-blind pilot trial (Alliance A22_Pilot9) to evaluate the effects of nanoemulsion curcumin (NEC, 200 mg/day) in postmenopausal women experiencing AIIA for ≥ 3 months.

A phase 1 trial of 8-chloro-adenosine in relapsed/refractory acute myeloid leukemia: An evaluation of safety and pharmacokinetics.

Background: This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 8-chloro-adenosine (8-Cl-Ado) in patients with relapsed/refractory acute myeloid leukemia (AML).

Methods: 8-Cl-Ado was administered daily for 5 days; the starting dose was 100 mg/m , the highest dose tested was 800 mg/m . The end points were toxicity, disease response, and PK/PD measurements.

An LC-MS/MS method for simultaneous determination of LB-100 and its active metabolite, endothall, in human plasma.

We have developed and validated a novel LC-MS/MS method for the simultaneous quantification of LB-100 and its active metabolite, endothall, in human plasma following solid-phase extraction. LB-105 and endothall-D6 were used as internal standards. Chromatographic separation was achieved on a Hypercarb™ column using 5 mM (NH)CO and 30:70 (v/v) 100 mM (NH)CO:acetonitrile as mobile phases.

Cell facilitation promotes growth and survival under drug pressure in breast cancer.

The interplay of positive and negative interactions between drug-sensitive and resistant cells influences the effectiveness of treatment in heterogeneous cancer cell populations. Here, we study interactions between estrogen receptor-positive breast cancer cell lineages that are sensitive and resistant to ribociclib-induced cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition. In mono- and coculture, we find that sensitive cells grow and compete more effectively in the absence of treatment.

Leflunomide Confers Rapid Recovery from COVID-19 and is Coupled with Temporal Immunologic Changes.

Background: Vaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone.

Mechanism-Driven and Clinically Focused Development of Botanical Foods as Multitarget Anticancer Medicine: Collective Perspectives and Insights from Preclinical Studies, IND Applications and Early-Phase Clinical Trials.

Cancer progression and mortality remain challenging because of current obstacles and limitations in cancer treatment. Continuous efforts are being made to explore complementary and alternative approaches to alleviate the suffering of cancer patients. Epidemiological and nutritional studies have indicated that consuming botanical foods is linked to a lower risk of cancer incidence and/or improved cancer prognosis after diagnosis.

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design.

Objectives: Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC.

Inflammation and Clinical Decline After Adjuvant Chemotherapy in Older Adults With Breast Cancer: Results From the Hurria Older Patients Prospective Study.

Purpose: Older breast cancer survivors are at increased risk of clinical decline after adjuvant chemotherapy. This study aimed to evaluate whether inflammatory markers assessed before adjuvant chemotherapy are associated with chemotherapy-induced clinical decline in a population of fit older adults with breast cancer.

Methods: In a prospective study of women age ≥ 65 years with stage I-III breast cancer treated with chemotherapy, we measured interleukin-6 (IL-6) and C-reactive protein (CRP) prechemotherapy (T1).

Off-the-shelf, steroid-resistant, IL13Rα2-specific CAR T cells for treatment of glioblastoma.

Background: Wide-spread application of chimeric antigen receptor (CAR) T cell therapy for cancer is limited by the current use of autologous CAR T cells necessitating the manufacture of individualized therapeutic products for each patient. To address this challenge, we have generated an off-the-shelf, allogeneic CAR T cell product for the treatment of glioblastoma (GBM), and present here the feasibility, safety, and therapeutic potential of this approach.

Methods: We generated for clinical use a healthy-donor derived IL13Rα2-targeted CAR+ (IL13-zetakine+) cytolytic T-lymphocyte (CTL) product genetically engineered using zinc finger nucleases (ZFNs) to permanently disrupt the glucocorticoid receptor (GR) (GRm13Z40-2) and endow resistance to glucocorticoid treatment.

Peritransplantation ruxolitinib administration is safe and effective in patients with myelofibrosis: a pilot open-label study.

We report results of our prospective pilot trial evaluating safety/feasibility of peritransplantation ruxolitinib for myelofibrosis treatment. Primary objectives were to determine safety and maximum tolerated dose (MTD) of ruxolitinib. Ruxolitinib was administered at 2 dose levels (DLs) of 5 and 10 mg twice daily, with fludarabine/melphalan conditioning regimen and tacrolimus/sirolimus graft-versus-host disease (GVHD) prophylaxis.

Development and validation of an LC-MS/MS generic assay platform for small molecule drug bioanalysis.

Aim: We developed a generic high-performance liquid chromatography mass spectrometry approach for quantitation of small molecule compounds without availability of isotopically labelled standard.

Methods: The assay utilized 50 μL of plasma and offers 8 potential internal standards (IS): acetaminophen, veliparib, busulfan, neratinib, erlotinib, abiraterone, bicalutamide, and paclitaxel. Preparation consisted of acetonitrile protein precipitation and aqueous dilution in a 96 well-plate format.

Systemic Anti-PD-1 Immunotherapy Results in PD-1 Blockade on T Cells in the Cerebrospinal Fluid.

Importance: Little is known about the penetration and bioactivity of systemically administered programmed cell death 1 (PD-1) antibodies in the central nervous system. Such information is critical for advancing checkpoint antibody therapies for treatment of brain tumors.

Objective: To evaluate pembrolizumab concentrations and PD-1 blockade on T cells in the cerebrospinal fluid (CSF) after intravenous administration.

Feasibility of intracerebrally administering multiple doses of genetically modified neural stem cells to locally produce chemotherapy in glioma patients.

Neural stem cells (NSCs) are tumor tropic and can be genetically modified to produce anti-cancer therapies locally in the brain. In a prior first-in-human study we demonstrated that a single dose of intracerebrally administered allogeneic NSCs, which were retrovirally transduced to express cytosine deaminase (CD), tracked to glioma sites and converted oral 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). The next step in the clinical development of this NSC-based anti-cancer strategy was to assess the feasibility of administering multiple intracerebral doses of CD-expressing NSCs (CD-NSCs) in patients with recurrent high-grade gliomas.

In vivo anticancer activity of a rhodium metalloinsertor in the HCT116 xenograft tumor model.

Mismatch repair (MMR) deficiencies are a hallmark of various cancers causing accumulation of DNA mutations and mismatches, which often results in chemotherapy resistance. Metalloinsertor complexes, including [Rh(chrysi)(phen)(PPO)]Cl (Rh-PPO), specifically target DNA mismatches and selectively induce cytotoxicity within MMR-deficient cells. Here, we present an in vivo analysis of Rh-PPO, our most potent metalloinsertor.

Evaluating Changes in Immune Function and Bone Microenvironment During Radium-223 Treatment of Patients with Castration-Resistant Prostate Cancer.

The effects of radium-223 on the immune system and the bone tumor microenvironment are incompletely understood. The authors describe mechanisms by which radium-223 may interact with the immune system, specifically through STAT-3 and impact on tumor and circulating lymphocyte populations. They review mechanisms through which effects of radium-223 and androgen-targeted therapy on bone microenvironment could be better elucidated.