A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas.

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted.

Associations between health-related fitness and patient-reported symptoms in newly diagnosed breast cancer patients.

BACKGROUND: Newly diagnosed breast cancer patients experience symptoms that may affect their quality of life, treatment outcomes, and survival. Preventing and managing breast cancer-related symptoms soon after diagnosis is essential. The purpose of this study was to investigate the associations between health-related fitness (HRF) and patient-reported symptoms in newly diagnosed breast cancer patients. METHODS: This study utilized baseline data from the Alberta Moving Beyond Breast Cancer Cohort Study that were collected within 90 days of diagnosis. HRF measures included peak cardiopulmonary fitness (peak volume of oxygen consumption (VO2peak)), maximal muscular strength and endurance, flexibility, and body composition. Symptom measures included depression, sleep quality, and fatigue. Adjusted multivariable logistic regression was performed for analyses. RESULTS: Of 1458 participants, 51.5% reported poor sleep quality, 26.5% reported significant fatigue, and 10.4% reported moderate depression. In multivariable-adjusted models, lower relative VO2peak was independently associated with a greater likelihood of all symptom measures, including moderate depression (p < 0.001), poor sleep quality (p = 0.009), significant fatigue (p = 0.008), any symptom (p < 0.001), and multiple symptoms (p < 0.001). VO2peak demonstrated threshold associations with all symptom measures such that all 3 lower quartiles exhibited similar elevated risk compared to the highest quartile. The strength of the threshold associations varied by the symptom measure with odds ratios ranging from ∼1.5 for poor sleep quality to ∼3.0 for moderate depression and multiple symptoms. Moreover, lower relative upper body muscular endurance was also independently associated with fatigue in a dose-response manner (p = 0.001), and higher body weight was independently associated with poor sleep quality in an inverted U pattern (p = 0.021). CONCLUSION: Relative VO2peak appears to be a critical HRF component associated with multiple patient-reported symptoms in newly diagnosed breast cancer patients. Other HRF parameters may also be important for specific symptoms. Exercise interventions targeting different HRF components may help newly diagnosed breast cancer patients manage specific symptoms and improve outcomes.

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition.

BACKGROUND: In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. METHODS AND RESULTS: Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes. CONCLUSIONS: Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.

Automated Whole Slide Imaging for Label-Free Histology Using Photon Absorption Remote Sensing Microscopy.

OBJECTIVE: Pathologists rely on histochemical stains to impart contrast in thin translucent tissue samples, revealing tissue features necessary for identifying pathological conditions. However, the chemical labeling process is destructive and often irreversible or challenging to undo, imposing practical limits on the number of stains that can be applied to the same tissue section. Here we present an automated label-free whole slide scanner using a PARS microscope designed for imaging thin, transmissible samples. METHODS: Peak SNR and in-focus acquisitions are achieved across entire tissue sections using the scattering signal from the PARS detection beam to measure the optimal focal plane. Whole slide images (WSI) are seamlessly stitched together using a custom contrast leveling algorithm. Identical tissue sections are subsequently H&E stained and brightfield imaged. The one-to-one WSIs from both modalities are visually and quantitatively compared. RESULTS: PARS WSIs are presented at standard 40x magnification in malignant human breast and skin samples. We show correspondence of subcellular diagnostic details in both PARS and H&E WSIs and demonstrate virtual H&E staining of an entire PARS WSI. The one-to-one WSI from both modalities show quantitative similarity in nuclear features and structural information. CONCLUSION: PARS WSIs are compatible with existing digital pathology tools, and samples remain suitable for histochemical, immunohistochemical, and other staining techniques. SIGNIFICANCE: This work is a critical advance for integrating label-free optical methods into standard histopathology workflows.

TITAN Trial: A Randomized Controlled Trial of a Cardiac Rehabilitation Care Model in Breast Cancer.

Background: Cardiac rehabilitation (CR) modeled care is recommended for patients with breast cancer to mitigate risk of cardiotoxicity. However, the cardiovascular impact of CR-modeled interventions has not been studied. Objectives: The purpose of this study was to evaluate if a multidisciplinary model of CR reduces cardiotoxicity and improves cardiovascular risk in patients undergoing breast cancer treatment. Methods: We randomly assigned patients with stage I to III breast cancer scheduled to receive anthracycline and/or trastuzumab-based chemotherapy to the CR intervention (n = 37) or usual care (n = 37). The intervention included guideline-directed management of cardiovascular risk factors, dietary counselling, and supervised exercise for 52 weeks. Cardiac magnetic resonance imaging, cardiopulmonary exercise testing, dual-energy x-ray absorptiometry, and serum biomarkers were acquired at baseline and 52 weeks. Results: There was no difference in the primary outcome, left ventricular ejection fraction (LVEF), between groups at 52 weeks (61% ± 6%). Other markers of cardiotoxicity, including high-sensitivity troponin I and brain natriuretic peptide, were similar between groups. However, total cholesterol (5.2 ± 0.8 mmol/L to 4.7 ± 0.8 mmol/L, P = 0.002) and low-density lipoprotein (3.0 ± 0.7 mmol/L to 2.4 ± 0.7 mmol/L, P < 0.001) decreased in the intervention group at 52 weeks and were unchanged in usual care. In all patients, adverse cardiac and metabolic changes occurred over 52 weeks including reductions in LVEF, left ventricular mass, high-density lipoprotein, lean body mass, insulin-like growth factor-1, as well as increased triglycerides, whole-body and truncal fat mass (all P < 0.050). Conclusions: The CR-modeled intervention had no effect on LVEF or biomarkers of cardiotoxicity. Future lifestyle intervention trials in patients with breast cancer should consider targeting other risk factors associated with incident cardiovascular disease. (Multidisciplinary Team IntervenTion in CArdio-ONcology [TITAN Study] [TITAN]; NCT01621659).