Hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin induces distinct transcriptomic changes in ovarian tumor and normal tissues.

Objective: To determine the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin on the transcriptomic profiles of normal and ovarian cancer (OC) tissues.
Methods: Normal and tumor samples from four OCs were prospectively collected pre- and immediately post-HIPEC treatment and subjected to RNA-sequencing. Differential gene expression, gene ontology enrichment and pathway analyses were performed. Heat shock protein and immune-response protein expression was assessed using protein arrays and western blotting.
Results: RNA-sequencing revealed 4231 and 322 genes significantly differentially expressed between pre- and post-treatment normal and OC tissues, respectively (both adjusted p-value <0.05). Gene enrichment analyses demonstrated that the most significantly upregulated genes in normal tissues played a role in immune as well as heat shock response (both adjusted p < 0.001). In contrast, HIPEC induced an increased expression of primarily heat shock response and protein folding-related genes in tumor tissues (both adjusted p < 0.001). HIPEC-induced heat shock protein (HSP) expression changes, including in HSP90, HSP40, HSP60, and HSP70, were also observed at the protein level in both normal and tumor tissues.
Conclusions: HIPEC with carboplatin resulted in an upregulation of heat shock-related genes in both normal and tumor tissue, with an additional immune response gene induction in normal and protein folding in tumor tissue. The findings of our exploratory study provide evidence to suggest that HIPEC administration may suffice to induce gene expression changes in residual tumor cells and raises a biological basis for the consideration of combinatorial treatments with HSP inhibitors.
Competing Interests: Declaration of Competing Interest G. Zoppoli reports receiving travel grants from Roche, Novartis, and Pfizer, consultation fees from Pfizer, reagents from ThermoFisher Scientific and Cytiva Life Sciences, outside the submitted work. N.R. Abu-Rustum reports Stryker/Novadaq and GRAIL grants paid to the institution, outside the current study. J.S. Reis-Filho reports receiving personal/consultancy fees from Goldman Sachs, REPARE Therapeutics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech and InVicro, outside the scope of this study. J.S. Reis-Filho has stocks or stock options with REPARE Therapeutics and Paige.AI. D.S. Chi reports membership of the medical advisory boards of Bovie Medical Co. (now Apyx Medical), Verthermia Inc. and Biom ‘Up, to have/had stock options of Bovie Medical Co. (now Apyx Medical), Verthermia Inc., Intuitive Surgical Inc. and TransEnterix Inc., and to be the Chief Editor and shareholder of C Surgeries. D. Zamarin reports personal/consulting fees from Agenus, Hookipa Biotech, Western Oncolytics, Synthekine, Mana Therapeutics, Xencor, Memgen and Takeda, grants and personal fees from Merck and from Astra Zeneca, grants and non-financial support from Genentech, grants from Plexxikon and stock options from Calidi Biotherapeutics, outside the submitted work. D. Zamarin has a patent for use of Newcastle Disease Virus for cancer therapy, outside the submitted work. Dr. Aghajanian reports membership of advisory boards/personal fees from Tesaro, Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca/Merck, Repare Therapeutics, and grants from Clovis, Genentech, AbbVie, Astra Zeneca, all outside the submitted work. R.E. O'Cearbhaill reports receiving honoraria/consulting/advisory role from GlaxoSmithKline, Fresenius, Seagen Inc., Carina Biotech and institutional research funding: Juno Therapeutics, Sellas Life Sciences, Ludwig Institute for Cancer Research, Stem CentRx, TapImmune Inc., TCR2 Therapeutics, Regeneron, Genmab, Atara Biotherapeutics, GlaxoSmithKline, AstraZeneca/Merck, Syndax, Genentech, Kite/Gilead, Gynecologic Oncology Group Foundation. Meal from AstraZeneca. B. Weigelt reports ad hoc membership of the scientific advisory board of Repare Therapeutics. The remaining authors have no conflicts of interest to declare.
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