Atta Goudarzi

The development of immunotherapy agents has revolutionized the field of oncology. The only FDA-approved immunotherapeutic approach in breast cancer consists of immune checkpoint inhibitors, yet several novel immune-modulatory strategies are being actively studied and appear promising. Innovative immunotherapeutic strategies are urgently needed in triple negative breast cancer (TNBC), a subtype of breast cancer known for its poor prognosis and its resistance to conventional treatments. TNBC is more primed to respond to immunotherapy given the presence of more tumor infiltrating lymphocytes, higher PD-L1 expression, and higher tumor mutation burden relative to the other breast cancer subtypes, and therefore, immuno-oncology represents a key area of promise for TNBC research. The aim of this review is to highlight current data and ongoing efforts to establish the safety and efficacy of immunotherapeutic approaches beyond checkpoint inhibitors in TNBC.

Osteosarcoma (OS) is the most common primary malignant tumor of the bone, and pulmonary metastasis is the most frequent cause of OS mortality. The aim of this study was to discover and characterize genetic networks differentially expressed in metastatic OS. Expression profiling of OS tumors, and subsequent supervised network analysis, was performed to discover genetic networks differentially activated or organized in metastatic OS compared to localized OS. Broad trends among the profiles of metastatic tumors include aberrant activity of intracellular organization and translation networks, as well as disorganization of metabolic networks. The differentially activated PRKCε-RASGRP3-GNB2 network, which interacts with the disorganized DLG2 hub, was also found to be differentially expressed among OS cell lines with differing metastatic capacity in xenograft models. PRKCε transcript was more abundant in some metastatic OS tumors; however the difference was not significant overall. In functional studies, PRKCε was not found to be involved in migration of M132 OS cells, but its protein expression was induced in M112 OS cells following IGF-1 stimulation.

ZRBA1 is a molecule termed 'combi-molecule' designed to induce DNA-alkylating lesions and to block epidermal growth factor receptor (EGFR) tyrosine kinase. Owing to its ability to downregulate the EGFR tyrosine kinase-mediated antiapoptotic signaling and DNA repair proteins, we inferred that it could significantly sensitize cells to ionizing radiation. Using the MDA-MB-468 human breast cancer cell line in which ZRBA1 has already been reported to induce significant EGFR/DNA-targeting potency, the results showed that: (i) concurrent administration of ZRBA1 and 4 Gy radiation led to a significant decrease in cell viability, (ii) the greater efficacy of the combination was sequential, being limited to conditions wherein the drug was administered concurrently with radiation or before radiation, and (iii) the efficacy enhancement of the combination was further confirmed by clonogenic assays from which a dose enhancement factor of 1.34 could be observed at survival fraction of 0.01. Flow cytometric analysis showed significant enhancement of cell cycle arrest in G2/M (P<0.046, irradiated cells vs. cells treated with ZRBA1 and radiation) and increased apoptosis when ZRBA1 was combined with radiation. Likewise, significant levels of double-strand breaks were observed for the combination, as determined by neutral comet assay (P<0.045, irradiated cells vs. cells treated with ZRBA1 and radiation). These results in toto suggest that the superior efficacy of the ZRBA1 plus radiation combination may be secondary to the ability of ZRBA1 to arrest the cells in G2/M, a cell cycle phase in which tumor cells are sensitive to radiation. Furthermore, the increased levels of DNA damage, combined with the concomitant downregulation of EGFR-mediated signaling by ZRBA1, may account for the significant levels of cell killing induced by the combination.

Abstract Introduction/ Background: GLP-1 agonists are an essential component of the anti-diabetes armamentarium. Common side effects include mild gastrointestinal distress and headaches. Uncommon side effects include acute pancreatitis and can limit use. We report a case of acute severe necrotizing pancreatitis most likely attributed to dulaglutide. Clinical Case: A 69-year-old man presented lethargic with diffuse abdominal pain associated with nausea and vomiting of 1-day duration. His past medical history consisted of type 2 diabetes, hyperlipidemia, hypertension, and hypothyroidism. His diabetes regimen included metformin, glipizide, and empagliflozin. Dulaglutide was added three months prior at 0.75 mg weekly, and the dose was increased to 1.5 mg weekly three days before presentation, the patient having received one such dose. Initial workup showed lipase 2800 units/mL, amylase 1185 units/mL, lactate 12.6 mmol/L, white blood cells 20 x 109/L, glucose 348 mg/dL, AST 30 unit/L, hematocrit 51.5%, blood urea nitrogen 24 mg/dL, and serum creatinine 1.57 mg/dL, calcium 8.1 mg/dL. No stones or CBD dilation were noted on ultrasound. Initial CT showed an enlarged pancreas with peripancreatic stranding and slightly diminished enhancement consistent with early signs of necrotizing pancreatitis. The patient became increasingly hypoxic and hypotensive and required intubation and triple pressor support to maintain adequate perfusion. On the second day of hospitalization, his hematocrit was 35.7%, blood urea nitrogen 37 mg/dL, calcium 6.8 mg/dL, and bicarbonate 21 mmol/L. AST and ALT peaked at 209 and 398 unit/L respectively. Calculated 48 hours Ranson’s score was 7. He completed 7 days of meropenem for necrotizing pancreatitis. He developed cholecystitis secondary to inflammatory damage of the biliary tract and received a cholecystostomy tube. A follow-up CT scan 7 days after the initial scan showed a prominent pancreas with extensive inflammation and without cysts, with several areas of nonenhancement/poor perfusion in the pancreatic head consistent with pancreatic necrosis. The patient made a full recovery and was discharged to a rehabilitation unit. Investigation into other causes of pancreatitis revealed triglycerides 104 mg/dL, a normal distribution of IgG subclasses (IgG4 36 mg/dL), no significant alcohol use, and no family history of pancreatitis. Conclusion: Pancreatic safety studies of dulaglutide have shown a good safety profile1. However, FDA safety warning exists on GLP-1 agonist prescriptions. Necrotizing pancreatitis with GLP-1a is rarely reported. We present a case of severe necrotizing pancreatitis due to dulaglutide use with the existence of temporality, after ruling out other causes of pancreatitis. Reference: 1. Nauck MA et al. Assessment of Pancreas Safety in the Development Program of Once-Weekly GLP-1 Receptor Agonist Dulaglutide. Diabetes Care 2017;40:647–54.

Significant efforts have been dedicated to developing controlled-release systems for the effective management of colorectal cancer. In this study, a once-daily, delayed-release regorafenib (REG) tablet was fabricated using 3D printing technology for the treatment of colorectal cancer. For this, a hydrogel containing 80 mg of the drug in a matrix of hyaluronic acid, carboxymethyl cellulose, Pluronic F127, and glycerol was prepared to incorporate into the shell cavity of tablet via a pressure-assisted microsyringe (PAM). The shell was printed from an optimized ink formulation of Soluplus®, Eudragit® RS-100, corn starch 1500, propylene glycol 4000, and talc through melt extrusion-based 3D printing. In vitro release assays showed a drug release rate of 91.1% in the phosphate buffer medium at 8 h and only 8.5% in the acidic medium. Drug release kinetics followed a first-order model. The results showed smooth and uniform layers based on scanning electron microscopy (SEM) and drug stability at 135 °C upon TGA. FTIR analysis confirmed the absence of undesired covalent interactions between the materials. Weight variation and assay results complied with USP standards. Mechanical strength testing revealed a Young’s modulus of 5.18 MPa for the tablets. Overall, these findings demonstrate that 3D printing technology enables the precise fabrication of delayed-release REG tablets, offering controlled-release kinetics and accurate dosing tailored for patients in intensive care units.