Satoshi Tamauchi

Mesothelial cells promote peritoneal invasion and metastasis of ascites-derived ovarian cancer cells through spheroid formation

Patients with epithelial ovarian cancer (EOC) are often diagnosed with peritoneal metastasis and ascites, the accumulation of intraperitoneal fluid containing nonmalignant cells. However, the interactions between EOC and nonmalignant cells before peritoneal metastasis remain unclear. To investigate this, whole EOC spheroids were observed using a multiphoton microscope, and their invasion ability was assessed. Mesothelial cells were identified as notable components of ascites through morphological assessment, immunohistochemical/immunofluorescence staining, and single-cell RNA sequencing analyses. Almost all EOC cells were spheroids, with 60% containing mesothelial cells. EOC cells quickly generate aggregated spheroids with mesothelial cells, and these aggregated cancer-mesothelial spheroids (ACMSs) invade collagen or mesothelial layers. Mesothelial cells forming ACMSs initiated the invasion. RNA sequencing analysis revealed marked RNA expression changes in mesothelial cells, whereas the changes in EOC cells were minor. Transforming growth factor–β1–stimulated mesothelial cells showed increased invadopodium formation along with fascin-1 up-regulation. These findings suggest that EOC cells alter mesothelial cells through ACMSs, thereby elucidating the rapid spread of EOC in the abdominal cavity.

Genomic insights and therapeutic efficacy of PARP inhibitors in a high-LOH patient-derived xenograft from malignant transformation of ovarian teratoma

The malignant transformation of ovarian mature cystic teratoma (MTMCT) is a rare and aggressive condition often diagnosed at advanced stages with limited treatment options. Leveraging cancer genomic profiling (CGP), this study evaluated the efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors in a patient-derived xenograft (PDX) model of MTMCT with high loss of heterozygosity (LOH). Tumor samples from a patient with MTMCT were used to establish the PDX model. CGP revealed high LOH and actionable mutations, including STK11 (E256*) and EMSY amplification, suggesting potential sensitivity to PARP inhibitors. Mice treated with PARP inhibitors exhibited significantly reduced tumor volumes compared to controls. Whole-exome sequencing (WES) performed on control and post-treatment residual tumors demonstrated that while total LOH levels remained stable, copy-neutral LOH (CN-LOH) increased significantly, indicating treatment-induced genomic instability. Notably, STK11 (E256*) underwent CN-LOH in residual tumors, suggesting a role in acquired resistance. Furthermore, EMSY amplification, initially observed in the tumor and associated with PARP inhibitor sensitivity, was absent after treatment, reflecting clonal selection or adaptive resistance. These findings underscore the therapeutic potential of PARP inhibitors in high-LOH MTMCT while highlighting the emergence of resistance mechanisms, including CN-LOH and loss of EMSY amplification. They emphasize the importance of considering tumor evolution and treatment timing when interpreting CGP results, providing a foundation for further research into predictive biomarkers and resistance mechanisms in rare gynecologic malignancies.

Annual Report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology: Annual Patient Report for 2022 and Annual Treatment Report for 2017

ABSTRACT Aim To provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2022 and the Annual Treatment Report for 2017, on the outcomes of patients who started treatment in 2017. Methods The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry, where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment with gynecologic malignancies was initiated in 2022 were analyzed retrospectively. Survival of the patients who started treatment with cervical, endometrial, and ovarian cancer in 2017 was analyzed by using the Kaplan–Meier, log–rank, and Wilcoxson tests. Results Treatment was initiated in 2022 for 8039 patients with cervical cancer, 14 518 with endometrial cancer, 8524 with ovarian, tubal, and peritoneal cancer, 2360 with ovarian borderline tumors, and with the others (270 vulvar cancer, 179 vaginal cancer, 539 uterine sarcoma, 48 uterine adenosarcoma, 158 trophoblastic diseases). This clinicopathological information was summarized as the Patient Annual Report. The 5‐year survival rates of the patients who initiated treatment in 2017 were as follows. For cervical cancer, the rates were 93.0%, 76.1%, 59.5%, and 28.3% for Stages I, II, III, and IV, respectively. For endometrial cancer, the rates were 94.9%, 88.8%, 72.7%, and 28.9% for Stages I, II, III, and IV, respectively. For ovarian cancer, the rates were 91.7%, 76.6%, 54.4%, and 45.2% for Stages I, II, III, and IV, respectively. Conclusion The annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan.

Annual report of the committee on gynecologic oncology, the Japan Society of Obstetrics and Gynecology: Annual patient report for 2021 and annual treatment report for 2016

AbstractAimTo provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2021 and the Annual Treatment Report for 2016, on the outcomes of patients who started treatment in 2016.MethodsThe Japan Society of Obstetrics and Gynecology maintains an annual tumor registry, where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment with gynecologic malignancies was initiated in 2021 were analyzed retrospectively. Survival of the patients who started treatment with cervical, endometrial, and ovarian cancer in 2016 was analyzed by using the Kaplan–Meier, log‐rank, and Wilcoxson tests.ResultsTreatment was initiated in 2021 for 8006 patients with cervical cancer, 13 912 with endometrial cancer, 8337 with ovarian, tubal, and peritoneal cancer, 2375 with ovarian borderline tumors, and with the others (226 vulvar cancer, 161 vaginal cancer, 437 uterine sarcoma, 47 uterine adenosarcoma, 160 trophoblastic diseases). This clinicopathological information was summarized as the Patient Annual Report. The 5‐year survival rates of the patients with cervical cancer were 92.3%, 77.0%, 56.1%, and 30.3% for stages I, II, III, and IV, respectively. The 5‐year survival rates for the patients with endometrial cancer were 94.1%, 88.8%, 71.2%, and 24.5% for stages I, II, III, and IV, respectively. The 5‐year survival rates for the patients with ovarian cancer (surface epithelial‐stromal tumors) were 91.3%, 78.8%, 54.3%, and 36.8% for stages I, II, III, and IV, respectively.ConclusionThe annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan.

Update on the oncologic and obstetric outcomes of medroxyprogesterone acetate treatment for atypical endometrial hyperplasia and endometrial cancer

Abstract Aims To evaluate the safety and effectiveness of high‐dose oral medroxyprogesterone acetate (MPA) therapy as a fertility‐sparing treatment for patients diagnosed with atypical endometrial hyperplasia (AEH) and endometrioid carcinoma G1 without myometrial invasion (G1EC). Particular attention was given to the extended administration and readministration of MPA for patients with persistent disease following initial treatment and those with recurrence. Methods We conducted a retrospective analysis of data from 79 patients who underwent daily oral MPA treatment between 2005 and 2024 at Nagoya University Hospital. Patient characteristics, treatment outcomes, factors contributing to recurrence, and post‐MPA therapy pregnancies were examined. Results MPA therapy achieved a remarkable complete response (CR) rate of 91.1%. The median time to achieve CR was 26.0 and 40.0 weeks for AEH and G1EC patients, respectively. Importantly, 27 patients (39.7%) attained CR after more than 6 months of treatment, including 8 patients (11.8%) who achieved CR after more than a year of treatment. The recurrence rates were 52.9% for AEH and 64.7% for G1EC. Twenty eight patients resumed MPA treatment, and 23 achieved second CR. Notably, recurrence was not associated with clinical factors such as age, body mass index, or post‐CR pregnancy. Among patients who attempted pregnancy after achieving CR, 22 live births were successfully achieved. Conclusions High‐dose oral MPA therapy demonstrated both safety and efficacy for preserving fertility in patients with AEH and G1EC, resulting in a high CR rate. MPA extension and readministration proved to be beneficial strategies for managing patients with recurrence and persistent disease following initial treatment.

Spatial distribution of tumor‐resident macrophages as predictive biomarkers in endometrial cancer

Abstract Background To investigate the role of CD47 expression and its relationship with tumor‐resident macrophages, specifically at the tumor margin, in patients with type II endometrial cancer. This study aims to elucidate whether CD47 could serve as a prognostic marker and to understand the dynamics between CD47 and macrophages, which could inform new therapeutic strategies. Methods A retrospective cohort study was conducted involving 75 patients of type II endometrial. Immunohistochemical analysis was performed to assess CD47 expression and macrophage markers (CD68 and CD163). Results The study found no direct correlation between CD47 expression levels and overall survival ( p  = 0.32), challenging its role as an independent prognostic marker in type II endometrial cancer. The higher expression of CD47 had significantly less incidence of endometrioid carcinoma G3 ( p  = 0.047). The negative correlation between CD47 H‐score and the density of CD68‐positive macrophages at tumor margin was statistically significant ( p  = 0.049). A high density of CD68‐positive macrophages at the tumor margin but a low density of CD163‐positive macrophages at the tumor margin were associated with poorer prognosis ( p  = 0.036). Conclusions The complex interaction between CD47 and macrophages, particularly at the tumor margin, suggests new avenues for targeted therapy in type II endometrial cancer.

Achievement of live birth after overcoming two gynecological malignancies treated with radical trachelectomy and medroxyprogesterone acetate therapy

AbstractCervical cancer is a human papilloma virus‐related disease, whereas endometrial cancer and atypical endometrial hyperplasia (AEH) are hormone‐related diseases, so co‐occurrence of the two is possible. However, scientific studies about such cases are rare. We encountered a case of cervical adenocarcinoma and AEH in a 33‐year‐old nulliparous woman. Two fertility‐sparing treatments were performed, a radical trachelectomy for the cervical cancer and high‐dose medroxyprogesterone acetate treatment for the AEH. After remission of the diseases, the patient became pregnant by in vitro fertilization and delivered a baby at 36 weeks' gestation by cesarean section. Although the patient had two uterine malignancies, proper evaluation of the diseases, consultation with the patient and her husband, and appropriate management led to fertility preservation, and live birth was achieved.

Downregulation of Chromosome 19 miRNA Cluster and the Tumor‐Suppressive Role of miR ‐517a‐3p in Choriocarcinoma

ABSTRACT Choriocarcinoma is a rare gynecologic malignancy. MicroRNAs, which are noncoding RNAs approximately 22 nucleotides in length, are known to regulate gene expression and play important roles in various cancers; however, their functions in choriocarcinoma remain largely unknown. This study aimed to identify disease‐specific microRNAs involved in choriocarcinoma development. Eleven cases of choriocarcinoma and five cases of complete hydatidiform mole treated at our institution were analyzed. Total RNA was extracted from trophoblast cells in formalin‐fixed, paraffin‐embedded specimens using laser capture microdissection, and microRNA sequencing was performed. The analysis revealed that 87 microRNAs were significantly upregulated, whereas 28 were downregulated in choriocarcinoma compared to complete hydatidiform mole. Notably, 13 of the 28 downregulated microRNAs belonged to the chromosome 19 microRNA cluster. In vitro experiments demonstrated that overexpression of miR‐517a‐3p, a representative member of this cluster, significantly suppressed cell proliferation, migration, and invasion in JEG‐3 and BeWo cell lines. Further transcriptome sequencing and computational analysis identified SRSF1 as a target gene of miR‐517a‐3p, which was validated by dual‐luciferase reporter assays. Knockdown of SRSF1 also led to significant reductions in proliferation, migration, and invasion, supporting its functional relevance. Immunohistochemical analysis confirmed that SRSF1 protein was highly expressed in choriocarcinoma tissues compared to complete hydatidiform mole. These findings indicate that downregulation of the chromosome 19 microRNA cluster is a characteristic feature of choriocarcinoma and that miR‐517a‐3p functions as a tumor suppressor by directly regulating SRSF1 expression.

Tumor growth direction predicts surgical difficulty in large uterine fibroids: A retrospective imaging‐based study

Abstract Objective To identify preoperative imaging features associated with retroperitoneal growth of large uterine fibroids and evaluate their impact on surgical outcomes. Methods This retrospective study included 20 patients who underwent hysterectomy for uterine fibroids measuring ≥10 cm between 2014 and 2024. Preoperative CT or MRI was evaluated for four features: bladder displacement, sigmoid colon deviation, cecal displacement, and hydronephrosis. Tumor growth direction (intraperitoneal vs. retroperitoneal) was determined intraoperatively. Operative time, blood loss, and complications were compared between groups. Results Eight tumors exhibited retroperitoneal growth. Bladder displacement, cecal shift, sigmoid colon deviation, and hydronephrosis were significantly more common in retroperitoneal cases (all p  < 0.05). Retroperitoneal tumors were associated with significantly greater median blood loss (1591 mL vs. 651 mL, p  = 0.043), although operative time did not differ significantly (301 vs. 232 min, p  = 0.237). Organ injury or resection occurred only in the retroperitoneal group. A bubble plot illustrated the trend of increased surgical burden in retroperitoneal cases. Conclusion Retroperitoneal growth of large uterine fibroids is associated with increased intraoperative blood loss and surgical complexity. Four simple imaging features may serve as reliable indicators of growth direction and help guide preoperative planning.

Niraparib as a therapeutic agent for the treatment of ovarian cancer meningeal dissemination with BRCA1 mutation

AbstractThis study analyzed a 63‐year‐old woman with hereditary BRCA1 mutation. She underwent interval debulking surgery after neoadjuvant chemotherapy for high‐grade serous ovarian carcinoma (HGSOC). After 2 years of postoperative chemotherapy, she developed headache and dizziness, and a suspected metastatic cerebellar mass in left ovary was detected. Pathological analysis of the mass revealed HGSOC, which was removed surgically. Eight months and another 6 months after the surgery, local recurrence was noted; hence, she underwent CyberKnife treatment. After 3 months, cervical spinal cord metastasis was found, evidenced by left shoulder pain. Moreover, meningeal dissemination was present around the cauda equina. Chemotherapy treatment, including bevacizumab, was ineffective and increased lesions were observed. After CyberKnife treatment for the cervical spinal cord metastasis, niraparib was initiated for the meningeal dissemination. The cerebellar lesions and meningeal dissemination improved within 8 months of niraparib treatment. Although meningeal dissemination is challenging to treat, niraparib may be useful in BRCA‐mutated HGSOC.

Does uterine preservation affect survival outcomes of patients with stage I ovarian sex cord-stromal cell tumours? A multi-institutional study

Sex cord-stromal tumours of the ovary are relatively uncommon neoplasms that account for 3 % of all ovarian cancers. Uterine preservation with careful staging is achievable; however, conservative surgery remains controversial. This study examined the prognostic effects of uterine preservation in patients with stage I sex cord-stromal tumours. This retrospective cohort study was undertaken between January 1986 and February 2019, and the clinicopathological data of 4897 women with malignant ovarian tumours were collected. Seventy-seven patients with stage I sex cord-stromal tumours were eligible for inclusion. The characteristics and survival outcomes of these patients were examined. To investigate the prognostic effects of uterine-preserving surgery, baseline imbalances between patients with and without uterine-preserving surgery were adjusted using an inverse probability of treatment weighting with propensity scores composed of independent clinical variables. The mean ages of patients in the uterine-preserving surgery and non-uterine-preserving surgery groups were 39.8 and 57.8 years, respectively. After inverse probability of treatment weighting adjustments, no significant differences in overall survival (p = 0.205) or recurrence-free survival (p=0.071) were observed between the uterine-preserving surgery and non-uterine-preserving surgery groups. Estimated 10-year overall survival rates were 98.7 % in the uterine-preserving surgery group and 95.9 % in the non-uterine-preserving surgery group, and 10-year recurrence-free survival rates were 87.2 % in the uterine-preserving surgery group and 78.2 % in the non-uterine-preserving surgery group. Uterine-preserving surgery did not significantly affect the site of tumour recurrence. Uterine-preserving surgery may be a feasible surgical option for patients with stage I sex cord-stromal tumours. Further research is needed to guarantee prognostic accuracy and develop effective therapeutic approaches for sex cord-stromal tumours.

The impact of systematic retroperitoneal lymphadenectomy on long-term oncologic outcome of women with advanced ovarian clear-cell carcinoma

The impact of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced ovarian clear-cell carcinoma (CCC) who are optimally debulked. Between 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinoma were analyzed in a multi-institutional study. Among them, 166 optimally debulked women with stage IIB-IV CCC were collected (residual tumor of <1 cm). All patients were divided into 2 groups: 1) Group I (n=112): underwent standard radical surgery with SRL, 2) Group II (n=54): underwent non-staging limited surgery. The pathological slides were assessed based on central pathological review. Oncologic outcomes were compared between the two groups using a propensity score (PS)-matching technique to adjust for various clinicopathologic factors. The median follow-up duration of all surviving women was 52.8 (1.6-184.2) months. Overall, 88 patients (53.0%) experienced recurrence and 68 patients (41.0%) died of the disease. In the original cohort, the 5-year overall survival (OS) rates of groups I and II were 57.9 and 64.9%, respectively (log-rank p=0.415). In the PS-adjusted cohort, the 5-year OS rates were 64.9 and 58.8% in women in groups I and II, respectively (p=0.453). Furthermore, in the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the 2 groups (group I vs. group II; hazard ratio=1.170; 95% confidence interval=0.633-2.187; p=0.615). This study suggests that the performance of SRL including radical surgery may not lead to a significant improvement in the oncologic outcome of advanced CCC patients with optimal cytoreduction.

Impact of incomplete surgery and adjuvant chemotherapy for the intraoperative rupture of capsulated stage I epithelial ovarian cancer: a multi-institutional study with an in-depth subgroup analysis

The aim of the present study was to examine the effects of incomplete surgery and adjuvant chemotherapy on the prognosis of patients with intraoperative rupture of capsulated stage I epithelial ovarian cancer (OvCa). A regional retrospective study was conducted between 1986 and 2019. Among 4,730 patients with malignant ovarian tumors, 534 women with International Federation of Gynecology and Obstetrics stage IA and IC1 epithelial OvCa were eligible. Differences in survival outcomes were examined between patients with stage IA and IC1 tumors and the effects of uterine preservation, complete-staging lymphadenectomy, and adjuvant chemotherapy were investigated by an in-depth subgroup analysis. To analyze therapeutic effects, baseline imbalances were adjusted using propensity score (PS). The prognosis of patients with stage IC1 tumors was worse than those with stage IA. Surgical spill did not affect the site of recurrence. In the PS-adjusted subgroup analysis, uterine preservation (hazard ratio [HR]=1.669; 95% confidence interval [CI]=1.052-2.744), incomplete-staging lymphadenectomy (HR=1.689; 95% CI=1.211-2.355), and the omission of adjuvant chemotherapy (HR=3.729; 95% CI=2.090-6.653) significantly increased the HR of recurrence for patients with stage IC1 tumors compared to those with stage IA tumors. Adjuvant chemotherapy decreased the impact of rupture with uterine preservation (HR=0.159; 95% CI=0.230-1.168) or incomplete-staging lymphadenectomy (HR=0.987; 95% CI=0.638-1.527). The present results suggest intraoperative rupture of capsulated stage I epithelial OvCa is associated with a poor prognosis. When chemotherapy is given for patients receiving incomplete surgery, there is no longer an increased risk of recurrence observed with the rupture.

Survival benefits of retroperitoneal lymphadenectomy for optimally-resected advanced ovarian high-grade serous carcinoma: a multi-institutional retrospective study

The survival benefits of retroperitoneal lymphadenectomy (RLNA) for epithelial ovarian cancer (EOC) remain controversial because clinical behaviors differ among subtypes. The purpose of the present study was to clarify whether RLNA increases the survival rate of advanced high-grade serous carcinoma (HGSC). This was a retrospective cohort analysis of 3,227 patients with EOC treated between 1986 and 2017 at 14 institutions. Among them, 335 patients with stage IIB-IV HGSC who underwent optimal cytoreduction (residual tumor of <1 cm) were included. Patients were divided into the RLNA group (n=170) and non-RLNA group (n=165). All pathological slides were assessed based on a central pathological review. Oncologic outcomes were compared between the two groups in the original and weighted cohorts adjusted with the inverse probability of treatment weighting. The median observation period was 49.8 (0.5-241.5) months. Overall, 219 (65%) out of 335 patients had recurrence or progression, while 146 (44%) died of the disease. In the original cohort, RLNA was a significant prognostic factor for longer progression-free survival (PFS) (hazard ratio [HR]=0.741; 95% confidence interval [CI]=0.558-0.985) and overall survival (OS) (HR=0.652; 95% CI=0.459-0.927). In the weighted cohort in which all variables were well balanced as standardized differences decreased, RLNA was also a significant prognostic factor for more favorable oncologic outcomes (PFS, adjusted HR=0.742; 95% CI=0.613-0.899) and OS, adjusted HR=0.620; 95% CI=0.488-0.787). The present study demonstrated that RLNA for stage III-IV HGSC with no residual tumor after primary debulking surgery contributed to better oncologic outcomes.

The influence of radical trachelectomy on endometrial thickness in in vitro fertilization‐embryo transfer

AbstractAimBoth morbidity and mortality rates of cervical cancer are increasing, especially in reproductive‐aged women. Radical trachelectomy (RT) is an effective fertility‐preserving surgery for early‐stage cervical cancer. This study aimed to determine the influence of RT on endometrial thickness during in vitro fertilization‐embryo transfer (IVF‐ET).MethodsForty‐four patients had undergone RT, and 23 women undergoing IVF‐ET treatment (105 ET cycles) were included. Endometrial thickness during hormone replacement therapy (HRT) was retrospectively evaluated and compared between patients with and without RT.ResultsEleven patients (50 ET cycles) in the RT group and 12 (52 ET cycles) in the control group were investigated. Compared with the control group, higher ET cancellation rates were observed in patients in the RT group (1 of 52 cycles [control group] vs. 8 of 50 cycles [RT group], p &lt; 0.01). Endometrial thinning was not affected by patient age at first IVF‐ET treatment, history of artificial abortion, preservation of uterine arteries during RT, or postoperative chemotherapy (p = 0.27, 1, 1, and 1, respectively).ConclusionsOur data revealed that RT influenced endometrial thickness in IVF‐ET. This was not affected by the background of the patients or perioperative management in this study. We could not reveal the underlying mechanism, but it is postulated that the transient postoperative uterine blood flow status and postoperative infections may have some effect on the endometrium. To resolve these issues, accumulation of evidences are required. We recommend informing patients about the impact of RT on IVF‐ET before starting assisted reproductive technology (ART).

An update of oncologic and obstetric outcomes of radical trachelectomy for early‐stage cervical cancer: The need for further minimally invasive treatment

AbstractAimsTo investigate the oncologic and obstetric outcomes of radical trachelectomy (RT) in patients with early‐stage cervical cancer and to evaluate the potential role of fertility‐preserving treatments in improving pregnancy outcomes while oncologic status is stable.MethodsIn this single‐institution study, we analyzed the oncologic and obstetric outcomes of 67 patients with early‐stage cervical cancer who underwent RT at Nagoya University Hospital.ResultsThe cancer recurrence rate (6.0%) and the mortality rate (1.5%) were comparable with those of previous studies. Of the 46 patients who attempted to conceive after RT, 19 (41.3%) became pregnant, and 16 gave birth. Of these 37.5% delivered at term, and delivery at less than 28 weeks of gestation occurred in 31.3% of pregnancies.ConclusionsRT is a viable treatment option for selected patients with early‐stage cervical cancer. However, the use of less invasive techniques, such as conization/simple trachelectomy and pelvic lymph node dissection, may improve pregnancy outcomes while oncologic status is stable.

In‐Tumor CRISPR ‐Cas9 Knockout Screening and Novel Therapy Development for Malignant Transformation of Ovarian Teratoma

ABSTRACT Malignant transformation of mature cystic teratoma (MTMCT) of the ovary is a rare but aggressive malignancy for which no standardized chemotherapy or effective targeted therapies currently exist. To identify therapeutic vulnerabilities in MTMCT, we performed a genome‐wide CRISPR‐Cas9 knockout screen using the MTMCT‐derived NOSCC1 cell line. Two parallel selective pressures were applied: in vivo tumorigenicity in immunodeficient mice and cisplatin exposure in vitro. From this screen, 67 negatively selected genes were identified, among which SOD1 and NDUFB4 emerged as top candidates based on high basal expression levels and clinical relevance. Integration with spatial transcriptomic data from three independent MTMCT patient tumors further supported the prioritization of these targets. SOD1 was selected for further investigation due to the availability of known pharmacological inhibitors. Both siRNA‐mediated knockdown and small‐molecule inhibition of SOD1 using LCS‐1 significantly suppressed MTMCT cell proliferation in vitro by inducing oxidative stress and impairing cell cycle progression. This antiproliferative effect was reversed by co‐treatment with N ‐acetylcysteine, a reactive oxygen species scavenger. In vivo validation using patient‐derived xenograft models demonstrated that oral administration of LCS‐1 led to significant tumor growth suppression and increased expression of apoptotic and DNA damage markers, including cleaved caspase‐3 and γH2AX. These findings establish SOD1 as a critical vulnerability in MTMCT and provide preclinical evidence supporting redox modulation as a therapeutic strategy for this highly chemoresistant and understudied ovarian cancer subtype. Our integrative approach combining functional genomics, spatial transcriptomics, and pharmacologic validation offers a framework for the discovery of novel targets in rare gynecologic malignancies.