abacavir and Stomach-Neoplasms

Yin Yang 1 (YY1) is a ubiquitous transcription factor with both transcriptional activating and repressing functions. Targeting YY1 is considered as a potential therapeutic strategy for several malignancies. Telomerase Reverse Transcriptase (TERT) is also considered as a potential target for cancer therapeutics. To enable the large-scale screening and identification of potential YY1 targeting drugs, a gastric cancer cell line-based drug screening assay was developed. In a YY1 targeted drug repurpose screen, abacavir sulfate, a nucleoside analog reverse transcriptase inhibitor, known to target TERT was identified to show the feature of activating YY1 mediated transcription. We further explored i) the molecular targets of abacavir, ii) activation pattern of pathways regulated by abacavir in gastric tumors, and iii) therapeutic potential of abacavir for gastric cancer cells. Oncogenic signaling pathways like MYC, HIF1-α, ERK, WNT, E2F, NFκB and NRF1/2 were also found to be highly activated by abacavir. Abacavir was found to have less impact on the viability of gastric cancer cells. Across gastric tumors, we observed the co-activation of TERT, alternative lengthening of telomere (ALT), DNA repair, and the oncogenic pathways MYC, E2F/DP1, ERK, YY1, HIF1α, and NFκB specific gene-sets, in a subset of gastric tumors. The observed connectivity among TERT, DNA repair, and multiple oncogenic pathways indicate the need for the development of combinatorial therapeutics for the gastric tumors with the activated TERT.

Topics: Antineoplastic Agents; Cell Death; Cell Line, Tumor; Dideoxynucleosides; Drug Repositioning; Humans; Reverse Transcriptase Inhibitors; Signal Transduction; Stomach Neoplasms; Telomerase; YY1 Transcription Factor

Alternative modes of antiretroviral administration are sought for people with impaired intestinal passage and/or absorption. We present a case of late HIV diagnosis (CD4+ count 160 cells/µL) with gastric outlet obstruction due to stomach adenocarcinoma. Co-morbidities included oesophageal candidiasis, Helicobacter pylori-positive duodenal ulcers and cytomegalovirus duodenitis. The gastric outlet obstruction required total parenteral nutrition and parenteral medication during four weeks of diagnostic work-up leading to pyloric resection. Crushed dolutegravir, abacavir and lamivudine were administered during this time in the evening via nasogastric tube, which was kept clamped overnight. The tube was unclamped in the morning and stomach content was drained during the daytime. This mode of administration resulted in rapid and sustained viral load suppression (from 300,000 to 115 copies per mL in 28 days, 81 copies/mL after 42 days of treatment and less than 40 copies/mL thereafter). Therapeutic drug monitoring confirmed sufficient antiretroviral plasma levels during this mode of administration. The absorption of crushed dolutegravir, abacavir and lamivudine in the stomach may be considered in people with questionable gastrointestinal passage or impaired gastric emptying to achieve viral load suppression.

Topics: Adenocarcinoma; Anti-Retroviral Agents; Dideoxynucleosides; Gastric Outlet Obstruction; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Intubation, Gastrointestinal; Lamivudine; Male; Middle Aged; Oxazines; Parenteral Nutrition; Piperazines; Pyridones; Stomach Neoplasms; Sustained Virologic Response; Treatment Outcome