Ovarian cancer resistance to PARPi and platinum-containing chemotherapy

Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies. Although initial response to therapy is observed, recurrence and ultimately chemoresistance result in overall therapeutic failure. This pattern has been evident with platinum therapy since the 1980s. Significant excitement surrounded the approval of poly (ADP-ribose) polymerase inhibition (PARPi) as a novel therapeutic option, especially with the advent of personalized medicine, but resistance has similarly developed to these treatments. Novel agents are constantly being sought, but if the obstacle of chemoresistance remains, the durability of responses will remain tenuous. Unraveling the multifactorial mechanisms of platinum and PARPi resistance is increasingly important as a therapeutic failure with current strategies is almost assured. Focusing greater efforts on expanding the current understanding of the complex nature of platinum and PARPi chemoresistance has tremendous potential to improve clinical outcomes

A prospective pilot study on the incidence of post-operative lymphedema in women with endometrial cancer

To determine the incidence of lower-extremity lymphedema after surgical therapy including lymphadenectomy in endometrial cancer patients using standardized leg measurements. Also, to determine additional risk factors for the development of lymphedema and to study the effect of lymphedema on one's quality of life. In this prospective cohort study, patients with the diagnosis of endometrial cancer who were to undergo definitive surgical management were evaluated pre-operatively and followed post-operatively over the course of two years. Standardized leg measurements were performed by the same individuals at six time-points. Subjects also completed a standardized quality-of-life survey at each time-point. The incidence of lymphedema in 39 women with endometrial cancer using a standardized leg measurement protocol was 12.8% with lymphedema defined as a 20% increase in post-operative leg measurements. There was no significant association between the development of lymphedema and the number of pelvic or para-aortic lymph nodes removed, medical comorbidities, or surgical approach (p > 0.05). Of the five patients who met criteria for lymphedema, only one had worsening quality-of-life concerns post-operatively on the FACT-En, version 4, survey. This is the first prospective study using standardized leg measurements to calculate the incidence of post-operative lymphedema in endometrial cancer. Medical comorbidities, surgical approach, number of lymph nodes removed, and location of lymph nodes removed did not appear to affect the development of lymphedema in this cohort. A prospective, multicenter trial is needed to confirm these findings and to further assess the impact of lymphedema on one's quality of life

A case series of triplet anti-hormonal therapy in androgen receptor-positive recurrent adult ovarian granulosa cell tumor

Therapeutic options for recurrent adult granulosa cell tumors (AGCT) are limited. After examining the hormonal pathways involved in FOXL2-mutated granulosa cell tumor development, a novel treatment regimen was utilized for recurrent AGCT: a combination of an androgen receptor antagonist, a gonadotropin-releasing hormone receptor agonist, and an aromatase inhibitor for hormonal blockade. In this case series, seven patients at our institution were treated with bicalutamide 50 mg orally once daily, Leuprolide acetate 7.5 mg intramuscular (IM) injection every 4 weeks, and a daily oral aromatase inhibitor. These patients had recurrent AGCT with androgen receptor positive tumors and had failed prior aromatase inhibitor therapy. All patients had undergone multiple surgical resections and many cycles of chemotherapy. Patients were monitored for toxicities and for response to treatment. Of the seven patients receiving the triple therapy, six saw clinical benefit. Two patients demonstrated a partial response and four patients had stable disease. One patient had progressive disease on the regimen. For the two patients who had a partial response to the triple therapy, there was strong expression of the androgen receptor (AR) noted on tumor immunohistochemistry. This drug combination was well-tolerated except for severe hot flashes in one patient. In conclusion, the triple therapy combination of an androgen receptor antagonist, aromatase inhibitor, and GnRH agonist demonstrated measurable responses in patients with recurrent AGCTs after multiple previous treatments. A prospective clinical trial is planned to further investigate these findings

Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance

Ovarian cancer is the most lethal gynecological malignancy among women worldwide and is characterized by aggressiveness, cancer stemness, and frequent relapse due to resistance to platinum-based therapy. Ovarian cancer cells metastasize through ascites fluid as 3D spheroids which are more resistant to apoptosis and chemotherapeutic agents. However, the precise mechanism as an oncogenic addiction that makes 3D spheroids resistant to apoptosis and chemotherapeutic agents is not understood. To study the signaling addiction mechanism that occurs during cancer progression in patients, we developed an endometrioid subtype ovarian cancer cell line named ‘MCW-OV-SL-3’ from the ovary of a 70-year-old patient with stage 1A endometrioid adenocarcinoma of the ovary. We found that the cell line MCW-OV-SL-3 exhibits interstitial duplication of 1q (q21–q42), where this duplication resulted in high expression of the PIK3C2B gene and aberrant activation of PI3K-AKT-ERK signaling. Using short tandem repeat (STR) analysis, we demonstrated that the cell line exhibits a unique genetic identity compared to existing ovarian cancer cell lines. Notably, the MCW-OV-SL-3 cell line was able to form 3D spheroids spontaneously, which is an inherent property of tumor cells when plated on cell culture dishes. Importantly, the tumor spheroids derived from the MCW-OV-SL-3 cell line expressed high levels of c-Kit, PROM1, ZEB1, SNAI, VIM, and Twist1 compared to 2D monolayer cells. We also observed that the hyperactivation of ERK and PI3K/AKT signaling in these cancer cells resulted in resistance to cisplatin. In summary, the MCW-OV-SL3 endometrioid cell line is an excellent model to study the mechanism of cancer stemness and chemoresistance in endometrioid ovarian cancer

Correction: Parashar et al. Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance. Cancers 2022, 14, 958

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