Heidi Pargas

Introduction: Ovarian cancer is a form of highly metastatic cancer that affects women aged 50-60 years old with Ashkenazi Jewish, Icelandic, or French decent^1,2. Factors leading to the development of ovarian cancer are increased repeat of ovulation due to reactive oxygen species (ROS) causing DNA damage, and/or mutations in the BRCA1 and BRCA2 known as the Hereditary Breast and Ovarian Cancer Syndrome^1,3. Once the mutations have formed, the tumor microenvironment, mostly composed of Tumor Associated Macrophages (TAMSs), forms⁴. TAMs take on the factions of M2 macrophages who contain MDR1 pumps¾ pivotal for chemoresistance; miRNAs are useful in activating this polarization⁵. Methods: A miR-21 mimic and inhibitor were transfected using lipo3000 into M1 and M2 cancer cell cultures⁵. Western blot and flow cytometry were used to analyze TAM polarization by Collagen Triple Helix Repeat Containing-1 (CTHRC1)⁶. The clinical trial consisted of dose-escalation to determine maximum tolerated dose and dose-expansion to determine objective response rate. Patients were given a starting dose of 100mg of Emactuzumab slowly increasing it to 3000 mg over 1.5 hours at q2w. In the dose-expansion, a dose of 1000mg of Emactuzumab was given at q2w⁷. Results: The miR-21 mimic infiltrated M2 cells more allowing for increased expression of M2 markers such as CD206 and CCL22. The miR-21 inhibitor downregulated M2 expression⁵. In the same way, CTHRC1 was caused proliferation and upregulation of TAMs and polarized them into M2-like macrophages. Infiltration markers CD68⁺ and CD163⁺ were analyzed and showed high infiltration percentages in the TAMs tested⁶. Emactuzumab in 1000mg doses was able to deplete TAMs in tissue without posing any safety issues. Also, Emactuzumab was able to reduce CSF-1R+ and CD163+ TAM which are M2-like markers⁷. Conclusion: miRNAs exhibited a direct link in TAM polarization leading to chemoresistance⁵. Downregulating certain miRNAs such as miRNA21, STAT6, through the CTHRC1 protein, and CSF-1, slowed the polarization of M2 macrophages ^5,8,6,9. The inhibition of these three mechanisms was effective in halting further polarization of M2 macrophages. A missing factor that stops these mechanisms from being effective is the reversion from M2 to M1 macrophages. Once a drug is developed that can both stop M2 polarization of new TAMs and revert those already polarized back to M1, real progress will be made against chemoresistance ovarian cancer⁷.

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