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Applied Research

Sunday Poster Presentation 1

P22: Peritoneal metastases from LAMN exhibit increased oxidative phosphorylation, and patient derived organoids are sensitive to metformin.

Sunday, February 18, 2024
8:35 AM - 8:40 AM AST
Location: Miramar I & II
Disclosure(s):
Eric Hanse, PhD: No financial relationships to disclose
Oliver Eng, MD: Tempus Labs, Inc.: Speaker (Ongoing)
Introduction: Low grade appendiceal neoplasms (LAMNs) are difficult to treat tumors which can disseminate throughout the abdomen, termed pseudomyxoma peritonei (PMP). PMP from LAMN is treated via cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but due to factors such as disease burden and location, optimal CRS may not be possible. In contrast to colorectal cancer (CRC), systemic cytotoxic therapies for the management of recurrent and/or unresectable disease from LAMN are not effective in improving survival. Therefore, there is a need to develop novel therapeutics for these tumors. The peritoneal cavity, a nutrient-limited environment devoid of blood, could represent a significant therapeutic vulnerability. Here, we sought to understand the genomic phenotype of LAMN better by examining expression profiles from tumors. Next, we developed a culture model of patient derived organoids (PDOs) to test new strategies for targeting PMP from LAMN. Using these two techniques we tested an inhibitor of oxidative phosphorylation (OXPHOS), metformin, on LAMN PMP PDOs as a therapeutic strategy.


Methods: We collected peritoneal tumor samples from both CRC and LAMN peritoneal metastases (PMs), performed RNASeq, and subsequent pathway analyses. For organoids, tumors were digested with collagenase and encapsulated in Matrigel. Medium was overlayed every other day. Metformin was treated for 72 hours.


Results: Results of RNASeq revealed one of the most up-regulated pathways in the LAMN patient tumor samples is oxidative phosphorylation (OXPHOS). Increased OXPHOS is developing as a hallmark of chemo-resistant tumors. Moreover, inhibiting OXPHOS with drugs has proven to be an effective strategy to re-sensitize chemo-resistant cells. PDOs have been shown to be reliable for predicting patient chemotherapeutic responses. Moreover, short-term culture of LAMN PDOs recapitulate chemo resistant phenotypes reported in vivo. We developed a long-term system to culture organoids collected from patient derived LAMN PMs. We then used the PDO system to test whether OXPHOS inhibition could limit the growth of LAMN PM PDOs. Following treatment with metformin, we found LAMN PM PDOs were severely growth restricted. These data suggest metformin could be a novel therapeutic strategy for PMs from LAMN.


Conclusions:

LAMN PMs increase OXPHOS compared to CRC PM chemo sensitive tumors. We developed a PDO model to target OXPHOS therapeutically. Our preliminary results suggest metformin is a potential therapeutic avenue to pursue in patients with PMP from LAMN.

Learning Objectives:

  • Get a sense of the metabolic differences chemo resistant LAMN exhibit compared to chemo sensitive peritoneal metastasis.
  • Understand how patient derived organoids for LAMN are important for predicting chemo therapeutic responses.
  • understand that LAMN is a metabolic disease that exhibits increased oxidative phosphorylation and that inhibition of this pathway with metformin may be a novel therapeutic option.