ONC201/TIC10 plus TLY012 anti-cancer effects via apoptosis inhibitor downregulation, stimulation of integrated stress response and death receptor DR5 in gastric adenocarcinoma.

Gastric adenocarcinoma typically presents with advanced stage when inoperable. Chemotherapy options include non-targeted and toxic agents, leading to poor 5-year patient survival outcomes. Small molecule ONC201/TIC10 (TRAIL-Inducing Compound #10) induces cancer cell death via ClpP-dependent activation of the integrated stress response (ISR) and up-regulation of the TRAIL pathway. We previously found in breast cancer, pancreatic cancer and endometrial cancer that ONC201 primes tumor cells for TRAIL-mediated cell death through ISR-dependent upregulation of ATF4, CHOP and TRAIL death receptor DR5. We investigated the ability of ONC201 to induce apoptosis in gastric adenocarcinoma cells in combination with recombinant human TRAIL (rhTRAIL) or PEGylated trimeric TRAIL (TLY012). AGS (caspase 8-, KRAS-, PIK3CA-mutant, HER2-amplified), SNU-1 (KRAS-, MLH1-mutant, microsatellite unstable), SNU-5 (p53-mutant) and SNU-16 (p53-mutant) gastric adenocarcinoma cells were treated with ONC201 and TRAIL both in cell culture and in vivo. Gastric cancer cells showed synergy following dual therapy with ONC201 and rhTRAIL/TLY012 (combination indices < 0.6 at doses that were non-toxic towards normal fibroblasts). Synergy was observed with increased cells in the sub-G1 phase of the cell cycle with dual ONC201 plus TRAIL therapy. Increased PARP, caspase 8 and caspase 3 cleavage after ONC201 plus TRAIL further documented apoptosis. Increased cell surface expression of DR5 with ONC201 therapy was observed by flow cytometry, and immunoblotting revealed ONC201 upregulation of the ISR, ATF4, and CHOP. We observed downregulation of anti-apoptotic cIAP-1 and XIAP in all cells except AGS, and cFLIP in all cells except SNU-16. We tested the regimen in an organoid model of human gastric cancer, and in murine sub-cutaneous xenografts using AGS and SNU-1 cells. Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

Selecting Patients for Palliative Procedures in Oncology.

Surgical palliation in oncology can be defined as "procedures employed with non-curative intent with the primary goal of improving symptoms caused by an advanced malignancy," and is an important aspect of the end-of-life care of patients with incurable malignancies. Palliative interventions may provide great benefit, but they also carry high risk for morbidity and mortality, which may be minimized with careful patient selection. This can be done by consideration of the patient and his or her indication for the given intervention via open communication, as well as prediction of benefits and risks to define the therapeutic index of the operation or procedure.

Identifying lung cancer in patients with active pulmonary tuberculosis.

The diagnosis of lung cancer can be delayed in patients with a history of infection with pulmonary tuberculosis that present with new lesions on chest imaging, due to a high initial index of suspicion for mycobacterium tuberculosis complex rather than malignancy. This may lead to diagnosis of malignancy at a more advanced stage of the disease with subsequent increased morbidity and mortality. We reviewed the current literature to evaluate various methods of differentiating between a diagnosis of lung cancer and tuberculosis including radiography, computerized tomography (CT), positron emission tomography (PET) and various biological markers. We included only papers published in English. Based on current data, we recommend that patients established as high risk, according to the American Association of Thoracic Surgery, patients with age greater than or equal to 55 years and a smoking history of greater than or equal to 30 pack years, should be assessed with CT for underlying malignancy prior to beginning tuberculosis treatment, even in the presence of a clinical or microbiologic diagnosis of tuberculosis. In patients with equivocal CT findings, we recommend examination of tumor markers miR128, miR210, miR126 along with CEA, if these tests are at the clinician's disposal.