Platinum-resistant Ovarian Cancer Research Articles

Inhibition of palmitoyltransferase ZDHHC12 sensitizes ovarian cancer cells to cisplatin through ROS-mediated mechanisms.

Platinum-based therapies have revolutionized the treatment of high-grade serous ovarian cancer (HGSOC). However, high rates of disease recurrence and progression remain a major clinical concern. Impaired mitochondrial function and dysregulated reactive oxygen species (ROS), hallmarks of cancer, hold potential as therapeutic targets for selectively sensitizing cisplatin treatment. Here, we uncover an oncogenic role of the palmitoyltransferase ZDHHC12 in regulating mitochondrial function and ROS homeostasis in HGSOC cells. Analysis of The Cancer Genome Atlas (TCGA) ovarian cancer data revealed significantly elevated ZDHHC12 expression, demonstrating the strongest positive association with ROS pathways among all ZDHHC enzymes. Transcriptomic analysis of independent ovarian cancer datasets and the SNU119 cell model corroborated this association, highlighting a strong link between ZDHHC12 expression and signature pathways involving mitochondrial oxidative metabolism and ROS regulation. Knockdown of ZDHHC12 disrupted this association, leading to increased cellular complexity, ATP levels, mitochondrial activity, and both mitochondrial and cellular ROS. This dysregulation, achieved by the siRNA knockdown of ZDHHC12 or treatment with the general palmitoylation inhibitor 2BP or the fatty acid synthase inhibitor C75, significantly enhanced cisplatin cytotoxicity in 2D and 3D spheroid models of HGSOC through ROS-mediated mechanisms. Markedly, ZDHHC12 inhibition significantly augmented the anti-tumor activity of cisplatin in an ovarian cancer xenograft tumor model, as well as in an ascites-derived organoid line of platinum-resistant ovarian cancer. Our data suggest the potential of ZDHHC12 as a promising target to improve the outcome of HGSOCs in response to platinum-based chemotherapy.

Antibody–drug conjugates in ovarian cancer

SummaryOvarian cancer (OC) management presents a challenging scenario in clinical practice due to its late diagnosis, high recurrence rate, and dismal 5‑year survival rate of 45%—especially in platinum-resistant cases. Antibody–drug conjugates (ADCs) are novel drugs that enable the selective delivery of potent cytotoxic agents directly to tumor cells, thereby maximizing treatment effectiveness while minimizing harm to healthy cells. Recent studies have shown promising results in this regard. Mirvetuximab soravtansine achieved remarkable results in the MIRASOL trial, suggesting it as a potential new standard of care for folate receptor-α-positive platinum-resistant OC treatment. Furthermore, trastuzumab deruxtecan demonstrated promising results in the PanTumor02 trial, showing clinically meaningful efficacy across a broad spectrum of HER2-positive solid tumors. This review article explores the current state of ADCs in ovarian cancer and their potential to improve outcomes in patients with recurrent ovarian cancer, especially in the platinum-resistant setting.

Results of a randomised Phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer

BackgroundOCTOVA compared the efficacy of olaparib (O) versus weekly paclitaxel (wP) or olaparib + cediranib (O + C) in recurrent ovarian cancer (OC).AimsThe main aim of the OCTOVA trial was to determine the progression-free survival (PFS) of olaparib (O) versus the oral combination of olaparib plus cediranib (O + C) and weekly paclitaxel (wP) in recurrent ovarian cancer (OC).MethodsIn total, 139 participants who had relapsed within 12 months of platinum therapy were randomised to O (300 mg twice daily), wP (80 mg/m2 d1,8,15, q28) or O + C (300 mg twice daily/20 mg daily, respectively). The primary endpoint was progression-free survival (PFS) of olaparib (O) versus olaparib plus cediranib (O + C) or weekly paclitaxel (wP). The sample size was calculated to observe a PFS hazard ratio (HR) 0.64 in favour of O + C compared to O (20% one-sided type I error, 80% power).ResultsThe majority had platinum-resistant disease (90%), 22% prior PARPi, 34% prior anti-angiogenic therapy, 30% germline BRCA1/2 mutations. The PFS was increased for O + C vs O (O + C 5.4 mo (2.3, 9.6): O 3.7 mo (1.8, 7.6) HR = 0.73; 60% CI: 0.59, 0.89; P = 0.1) and no different between wP and O (wP 3.9 m (1.9, 9.1); O 3.7 mo (1.8, 7.6) HR = 0.89, 60% CI: 0.72, 1.09; P = 0.69). The main treatment-related adverse events included manageable diarrhoea (4% Grade 3) and hypertension (4% Grade 3) in the O + C arm.DiscussionOCTOVA demonstrated the activity of O + C in women with recurrent disease, offering a potential non-chemotherapy option.Trial registrationISRCTN14784018, registered on 19th January 2018 http://www.isrctn.com/ISRCTN14784018.

CircNUP50 is a novel therapeutic target that promotes cisplatin resistance in ovarian cancer by modulating p53 ubiquitination

BackgroundMost patients with ovarian cancer (OC) treated with platinum-based chemotherapy have a dismal prognosis owing to drug resistance. However, the regulatory mechanisms of circular RNA (circRNA) and p53 ubiquitination are unknown in platinum-resistant OC. We aimed to identify circRNAs associated with platinum-resistant OC to develop a novel treatment strategy.MethodsPlatinum-resistant circRNAs were screened through circRNA sequencing and validated using quantitative reverse-transcription PCR in OC cells and tissues. The characteristics of circNUP50 were analysed using Sanger sequencing, oligo (dT) primers, ribonuclease R and fluorescence in situ hybridisation assays. Functional experimental studies were performed in vitro and in vivo. The mechanism underlying circNUP50-mediated P53 ubiquitination was investigated through circRNA pull-down analysis and mass spectrometry, luciferase reporters, RNA binding protein immunoprecipitation, immunofluorescence assays, cycloheximide chase assays, and ubiquitination experiments. Finally, a platinum and si-circNUP50 co-delivery nanosystem (Psc@DPP) was constructed to treat platinum-resistant OC in an orthotopic animal model.ResultsWe found that circNUP50 contributes to platinum-resistant conditions in OC by promoting cell proliferation, affecting the cell cycle, and reducing apoptosis. The si-circNUP50 mRNA sequencing and circRNA pull-down analysis showed that circNUP50 mediates platinum resistance in OC by binding p53 and UBE2T, accelerating p53 ubiquitination. By contrast, miRNA sequencing and circRNA pull-down experiments indicated that circNUP50 could serve as a sponge for miR-197-3p, thereby upregulating G3BP1 to mediate p53 ubiquitination, promoting OC platinum resistance. Psc@DPP effectively overcame platinum resistance in an OC tumour model and provided a novel idea for treating platinum-resistant OC using si-circNUP50.ConclusionsThis study reveals a novel molecular mechanism by which circNUP50 mediates platinum resistance in OC by modulating p53 ubiquitination and provides new insights for developing effective therapeutic strategies for platinum resistance in OC.Graphical

Efficacy and safety of VEGF/VEGFR inhibitors for platinum-resistant ovarian cancer: a systematic review and meta-analysis of randomized controlled trials

BackgroundAlmost all patients with ovarian cancer will experience relapse and eventually develop platinum-resistant. The poor prognosis and limited treatment options have prompted the search for novel approaches in managing platinum-resistant ovarian cancer (PROC). Therefore, a meta-analysis was conducted to evaluate the efficacy and safety of combination therapy with vascular endothelial growth factor (VEGF) /VEGF receptor (VEGFR) inhibitors for PROC.MethodsA comprehensive search of online databases was conducted to identify randomized clinical trials published until December 31, 2022. Pooled hazard ratios (HR) was calculated for overall survival (OS) and progression-free survival (PFS), while pooled odds ratio (OR) was calculated for objective response rate (ORR) and treatment-related adverse events (TRAEs). Subgroup analysis was further performed to investigate the source of heterogeneity.ResultsIn total, 1097 patients from eight randomized clinical trials were included in this meta-analysis. The pooled HRs of OS (HR = 0.72; 95% CI: 0.62–0.84, p < 0.0001) and PFS (HR = 0.52; 95% CI: 0.45–0.59, p < 0.0001) demonstrated a significant prolongation in the combination group compared to chemotherapy alone for PROC. In addition, combination therapy demonstrated a superior ORR compared to monotherapy (OR = 2.34; 95%CI: 1.27–4.32, p < 0.0001). Subgroup analysis indicated that the combination treatment of VEGF/VEGFR inhibitors and chemotherapy was significantly more effective than monochemotherapy in terms of OS (HR = 0.71; 95% CI: 0.61–0.84, p < 0.0001), PFS (HR = 0.49; 95% CI: 0.42–0.57, p < 0.0001), and ORR (OR = 2.97; 95% CI: 1.89–4.67, p < 0.0001). Although the combination therapy was associated with higher incidences of hypertension, mucositis, proteinuria, diarrhea, and hand-foot syndrome compared to monochemotherapy, these toxicities were manageable and well-tolerated.ConclusionsThe meta-analysis demonstrated that combination therapy with VEGF/VEGFR inhibitors yielded better clinical outcomes for patients with PROC compared to monochemotherapy, especially when combined with chemotherapy. This analysis provides more treatment options for patients with PROC.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO], Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42023402050.

Abstract B027: Preclinical efficacy of Tumor Treating Fields (TTFields) applied with PARP inhibitors or carboplatin in ovarian cancer

Abstract Purpose: Ovarian cancer is the leading cause of death among cancers of the female reproductive system. Surgery and platinum-based adjuvant chemotherapy followed by PARP inhibitor (PARPi) maintenance therapy is standard treatment for most patients diagnosed with ovarian cancer. The mechanism of action of PARPi and platinum-based therapy involves the induction of DNA damage, which requires the Fanconi Anemia (FA)- BRCA pathway for repair, making these agents most beneficial in cancers with BRCA mutations. However, 75% of patients with ovarian cancer have BRCA wild type tumors and therefore their benefit from PARPi is limited. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cancer cell death. Recent research demonstrated TTFields induce a state of BRCAness in multiple cancer types, as well as anticancer effects in ovarian cancer preclinical models. This study investigated the impact of TTFields concomitant with carboplatin or PARPi in ovarian cancer cell lines. Methods: A2780 (BRCA wild type), OVCAR3 (BRCA mutated), and A2780cis (platinum-resistant) ovarian cancer cells were treated with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or concomitant with application of carboplatin or a PARPi (olaparib or niraparib). Efficacy assessments included cell count, colony formation, and apoptosis induction. The overall effect was calculated by multiplying the effects on cell count and colony formation. Results: TTFields treatment reduced cell count, increased overall effect, and elevated apoptosis. Carboplatin, olaparib, and niraparib exhibited dose-dependent effects in all cell lines. When TTFields were applied together with these drugs, a synergistic interaction was observed in the BRCA wild-type A2780 cells and platinum-resistant A2780cis cells, while an additive effect was noted in the BRCA mutant OVCAR-3 cells. Conclusions: This data implies potential advantages for TTFields concomitant with platinum-based chemotherapy and PARPi in ovarian cancer, even without underlying BRCA mutations. This aligns with the BRCAness state induced by TTFields and suggests a benefit in platinum resistant cancer. Overall, TTFields may augment the efficacy of ovarian cancer treatment in both adjuvant and maintenance settings. Citation Format: Antonia Martinez-Conde, Hila Ene, Kerem Ben-Meir, Roni Frechtel-Gerzi, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Preclinical efficacy of Tumor Treating Fields (TTFields) applied with PARP inhibitors or carboplatin in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B027.

N6-methyladenosine-modified circPLPP4 sustains cisplatin resistance in ovarian cancer cells via PIK3R1 upregulation

BackgroundCisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear.MethodsPlatinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo. The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH.ResultscircPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m6A) modification of circPLPP4. In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model.ConclusionsOur study reveals a plausible mechanism by which the m6A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.

High-expressed ACAT2 predicted the poor prognosis of platinum-resistant epithelial ovarian cancer

BackgroundAcetyl-CoA acetyltransferase 2 (ACAT2) is a lipid metabolism enzyme and rarely was researched in epithelial ovarian cancer (EOC).MethodsACAT2 expressions were confirmed in two pairs of cell lines (A2780 and A2780/DDP, OVCAR8 and OVCAR8/DDP) from Gene Expression Omnibus database by bioinformatics analysis, and in A2780 and A2780/DDP cell lines by quantitative real-time polymerase chain reaction and western blotting. Tissue samples were stained by immunohistochemistry and scored for ACAT2 expression. The relationships between ACAT2 expression and clinicopathological characteristics were analyzed by χ2 test. The prognosis of ACAT2 was analyzed by the log-rank tests and Cox regression models.ResultsACAT2 was remarkably upregulated in the above drug-resistant cell lines by mRNA (all P < 0.05) and protein expression (P = 0.026) than those in sensitive ones. Patients were classified as ACAT2-high (n = 51) and ACAT2-low (n = 26) according to immunohistochemical score. ACAT2 expression had a significantly inverse correlation with FIGO stage (P = 0.030) and chemo-response (P = 0.041). A marginal statistical significance existed in ACAT2 expression and ascites volume (P = 0.092). Univariate analysis suggested that high-expressed ACAT2 was associated with decreased platinum-free interval (PFI) (8.57 vs. 14.13 months, P = 0.044), progression-free survival (PFS) (14.12 vs. 19.79 months, P = 0.039) and overall survival (OS) (36.89 vs. 52.40 months, P = 0.044). Multivariate analysis demonstrated that ACAT2 expression (hazard ratio = 2.18, 95% confidence interval: 1.15–4.11, P = 0.017) affected OS independently, rather than PFI and PFS.ConclusionThe expression of ACAT2 in A2780/DDP and OVCAR8/DDP was higher than the corresponding A2780 and OVCAR8. High-expressed ACAT2 was associated with advanced FIGO stage, chemo-resistance, and decreased PFI, PFS and OS. It was an independent prognostic factor of OS in EOC.

Efficacy and safety of combined anlotinib-oral etoposide treatment for patients with platinum-resistant ovarian cancer.

Despite the availability of numerous treatment options, managing patients with platinum-resistant ovarian cancer (PROC) remains challenging, and the prognosis of PROC is notably unfavorable. This retrospective study aimed to assess the efficacy and safety of combined anlotinib-oral etoposide treatment for patients with PROC. Data of 23 patients who were diagnosed with PROC from January 2020 to November 2022 and treated with anlotinib combined with oral etoposide for at least 2 cycles were retrospectively analyzed. Among per-protocol patients, 9 (45.0%; 95% confidence interval [CI]=21.1-68.9) of 20 patients achieved partial response and 17 (85.0%, 95% CI=67.9-100.0) of 20 patients achieved disease control. The median progression-free survival was 8.7 months (95% CI=5.3-11.6). The incidence of adverse events (any grade) was 100%, and the incidence of grade 3-4 adverse events was 54.5%. Anlotinib combined with etoposide emerged effective for the treatment of PROC.

Impact of Bevacizumab on Clinical Outcomes in Patients With Platinum-resistant Relapsed Ovarian Cancer.

Over the past several decades, new anti-cancer drugs have been developed for the treatment of epithelial ovarian cancer. The development of drugs has led to changes in improving the prognosis of ovarian cancer patients. One of these drugs, bevacizumab, is used for advanced or recurrent ovarian cancer. In this study, we aimed to evaluate survival improvement in patients with platinum-resistant relapsed epithelial ovarian cancer (PR-ROC) after introduction of bevacizumab in real world experience. We retrospectively divided patients with PR-ROC into two groups: bevacizumab plus chemotherapy (BEV-CT group) and chemotherapy alone (CT group). Progression-free survival (PFS), the primary endpoint, between two groups was compared to evaluate whether survival outcomes were improved. In addition, overall survival (OS) was also compared. A total of 154 patients were included in the study: 57 and 97 patients in the BEV-CT and CT groups, respectively. OS was significantly longer in the BEV-CT group than in the CT group. The use of bevacizumab was identified as a favorable prognostic factor for OS. In a subgroup analysis confined to second-line chemotherapy, PFS and OS were statistically different between groups. More patients in the CT group suffered hematologic adverse events of grade 3 or above than patients in the BEV-CT group. In a real-world clinical setting, introduction of bevacizumab led to improvement of OS in patients with PR-ROC with a tolerable toxicity.

Mirvetuximab soravtansine in platinum-resistant recurrent ovarian cancer with high folate receptor-alpha expression: a cost-effectiveness analysis.

Mirvetuximab soravtansine (MIRV), a new antibody-drug conjugate, versus the investigator's choice of chemotherapy (IC) was the first treatment to demonstrate benefits for progression-free and overall survival in platinum-resistant recurrent ovarian cancer (PROC) with high folate receptor-alpha (high-FRα) expression. Efficacy, safety, and economic effectiveness make MIRV the new standard of care for these patients. Based on patients and clinical parameters from MIRASOL (GOG 3045/ENGOT-ov55) phase III randomized controlled trials, the Markov model with a 20-year time horizon was established to evaluate the cost and efficacy of MIRV and IC for PROC with high-FRα expression, considering the bevacizumab-pretreated situation from the American healthcare system. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental net health benefits were the main outcome indicators and compared with willingness-to-pay threshold of $100,000/QALY. Sensitivity and scenario analyses were conducted. Compared with the IC, MIRV was associated with incremental costs of $538,251, $575,674, and $188,248 with the corresponding QALYs (LYs) increased by 0.90 (1.55), 1.09 (1.88), and 0.53 (0.79), leading to ICERs of $596,189/QALY ($347,995/LY), $530,061/QALY ($306,894/LY), and $1,011,310/QALY ($680,025/LY) in the overall, bevacizumab-naïve, and bevacizumab-pretreated patients, respectively. When MIRV is reduced by more than 75%, it may be a cost-effective treatment. At the current price, MIRV for PROC with high-FRα expression is not the cost-effective strategy in the US. However, its treatment has higher health benefits in bevacizumab-naïve patients, which is likely to be an alternative.

PiR-1919609 Is an Ideal Potential Target for Reversing Platinum Resistance in Ovarian Cancer.

PIWI-interacting RNAs (piRNAs) are a type of noncoding small RNA that can interact with PIWI-like RNA-mediated gene silencing (PIWIL) proteins to affect biological processes such as transposon silencing through epigenetic effects. Recent studies have found that piRNAs are widely dysregulated in tumors and associated with tumor progression and a poor prognosis. Therefore, this study aimed to investigate the effect of piR-1919609 on the proliferation, apoptosis, and drug resistance of ovarian cancer cells. In this study, we used small RNA sequencing to screen and identify differentially expressed piRNAs in primary ovarian cancer, recurrent ovarian cancer, and normal ovaries. A large-scale verification study was performed to verify the expression of piR-1919609 in different types of ovarian tissue, including ovarian cancer tissue and normal ovaries, by RT-PCR and to analyze its association with the clinical prognosis of ovarian cancer. The expression of PIWILs in ovarian cancer was verified by RT-PCR, Western blotting and immunofluorescence. The effects of piR-1919609 on ovarian cancer cell proliferation, apoptosis and drug resistance were studied through in vitro and in vivo models. (1) piR-1919609 was highly expressed in platinum-resistant ovarian cancer tissues (p < 0.05), and this upregulation was significantly associated with a poor prognosis and a shorter recurrence time in ovarian cancer patients (p < 0.05). (2) PIWIL2 was strongly expressed in ovarian cancer tissues (p < 0.05). It was expressed both in the cytoplasm and nucleus of ovarian cancer cells. (3) Overexpression of piR-1919609 promoted ovarian cancer cell proliferation, inhibited apoptosis, and promoted tumor growth in nude mice. (4) Inhibition of piR-1919609 effectively reversed ovarian cancer drug resistance. In summary, we showed that piR-1919609 is involved in the regulation of drug resistance in ovarian cancer cells and might be an ideal potential target for reversing platinum resistance in ovarian cancer.

Synergistic Sensitization of High-Grade Serous Ovarian Cancer Cells Lacking Caspase-8 Expression to Chemotherapeutics Using Combinations of Small-Molecule BRD4 and CDK9 Inhibitors.

Ovarian cancer is one of the most lethal gynecological cancers worldwide, with approximately 70% of cases diagnosed in advanced stages. This late diagnosis results from the absence of early warning symptoms and is associated with an unfavorable prognosis. A standard treatment entails a combination of primary chemotherapy with platinum and taxane agents. Tumor recurrence following first-line chemotherapy with Carboplatin and Paclitaxel is detected in 80% of advanced ovarian cancer patients, with disease relapse occurring within 2 years of initial treatment. Platinum-resistant ovarian cancer is one of the biggest challenges in treating patients. Second-line treatments involve PARP or VEGF inhibitors. Identifying novel biomarkers and resistance mechanisms is critical to overcoming resistance, developing newer treatment strategies, and improving patient survival. In this study, we have determined that low Caspase-8 expression in ovarian cancer patients leads to poor prognosis. High-Grade Serous Ovarian Cancer (HGSOC) cells lacking Caspase-8 expression showed an altered composition of the RNA Polymerase II-containing transcriptional elongation complex leading to increased transcriptional activity. Caspase-8 knockout cells display increased BRD4 expression and CDK9 activity and reduced sensitivities to Carboplatin and Paclitaxel. Based on our work, we are proposing three potential therapeutic approaches to treat advanced ovarian cancer patients who exhibit low Caspase-8 expression and resistance to Carboplatin and/or Paclitaxel-combinations of (1) Carboplatin with small-molecule BRD4 inhibitors; (2) Paclitaxel with small-molecule BRD4 inhibitors, and (3) small-molecule BRD4 and CDK9 inhibitors. In addition, we are also proposing two predictive markers of chemoresistance-BRD4 and pCDK9.

First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors.

(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients (n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11-447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial.

Immunologic Signatures of Peripheral Blood T Cells Reveal the Outcome of p53MVA Vaccine and Pembrolizumab Treatment in Patients with Advanced Ovarian Cancer.

Our previous studies indicated that p53-reactive T cells were associated with clinical benefit in patients with advanced ovarian cancer who were treated with p53-expressing modified vaccinia Ankara (p53MVA) vaccine and gemcitabine chemotherapy. To replace chemotherapy with an approach that will enhance vaccine efficacy and antitumor immunity, we treated patients with p53MVA in combination with PD-1 checkpoint blocker, pembrolizumab. We also attempted to further characterize the activation status of T cells prior to vaccination and during treatment. Patients received up to three triweekly vaccinations concurrent with pembrolizumab, followed by pembrolizumab monotherapy at 3-week intervals. Correlative studies analyzed peripheral blood T-cell phenotypes and profiles of immune function gene expression. We observed 6/28 (21%) patients with a clinical benefit to therapy, including 3 partial responses (PR) and 3 patients with stable disease (SD) for 6+ months. The median progression-free survival was 1.8 months (95% confidence interval: 1.7-3.8) and median overall survival was 15.1 months (9.4-30.4). Two patients remain progression-free at 28 and 33 months. Of the 18 patients evaluable in correlative studies, 6 were immunologic responders of whom 5 had clinical benefit (3 PR, 2 SD). Immunologic non-responders expressed in pretreatment peripheral blood mononuclear cell samples high levels of mRNA for multiple molecules associated with terminally differentiated T cells. p53MVA/pembrolizumab immunotherapy showed promising antitumor activity in patients who demonstrated functionally competent peripheral blood T cells. Detection of markers of terminally differentiated T cells before treatment may identify patients unlikely to respond to p53MVA/pembrolizumab. The activity of a combination immunotherapy of p53 vaccine and PD-1 checkpoint blockade in patients with platinum-resistant ovarian cancer was evaluated in a phase II trial. Clinical benefit was correlated with the responsive immune status of patients before and during the treatment, defining potential predictive markers for immune therapy.

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer

BackgroundMirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody–drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States.MethodsWe conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator’s choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes.ResultsA total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P=0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%).ConclusionsAmong participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.)

Abstract IA014: From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma

Abstract IA014: From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma

Abstract LB_A13: Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer

Abstract Background: The MCT inhibitor CYT-0851 potently inhibits MCT1, has activity against MCT4, and blocks lactate transport resulting in cell death in glycolytic cancer cells. In an in vitro CRISPR screen, thymidylate synthetase was a significant hit in 2 resistant cell models, sensitizing them to CYT-0851. Follow-up in vitro combination studies showed that CYT-0851 synergized with 5-FU to inhibit cancer cell growth. Monotherapy clinical activity of CYT-0851 has been reported previously in lymphoma and solid tumors. In the phase 1 dose escalation trial of CYT-0851 plus cape, 400 mg was identified as the recommended phase 2 dose. In three phase 2 trials, cape had a RECIST response rate of 5-8% in ovarian cancer. Methods: An expansion cohort of 10 patients (pts) with platinum resistant advanced ovarian cancer were treated with CYT-0851, 400 mg QD in combination with cape, 1000 mg/m2 PO BID x 14 days every 21 days and were evaluable. One additional pt treated at the 300 mg dose level was evaluable and added to the analysis. The primary objective was safety, and secondary objectives were pharmacokinetics and preliminary anti-tumor activity by RECIST. Results: As of Aug 21, 2023, 11 pts were treated and evaluable, 9 white, 1 African American black, and 1 American Indian or Alaskan native, with a median age of 64 (range 52-76). Median prior therapies were 6 (range 2-14). All but one had 3 or more prior therapies. Median CYT-0851 dose compliance with continuous daily dosing was 99% (range 91– 100%). There were no treatment discontinuations or CYT-0851 dose reductions for treatment related adverse events. 7 pts (64%) experienced a treatment-related adverse event, all were Grade 1-2. There were no grade 3+ treatment related adverse events. The most common related AEs were fatigue reported in 5 pts (46%), and decreased appetite, diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome and vomiting, each reported in 2 patients (18%). Exposure of CYT-0851 in combination with capecitabine exhibits dose proportional behavior and was similar between combination therapy and monotherapy. One pt had a confirmed PR with progression on day 294, and 2 additional pts achieved a PR that has not been confirmed yet, with treatment ongoing on day 113 and 41. 7 pts had SD, and one patient PD as best response. The disease control rate was 91%. 5 Pts discontinued for progressive disease with a median of 133 days of treatment (range 43-300), and 2 withdrew consent on days 131-134. 4 patients continue therapy on days 42,47,106, and 113. Median PFS was 170 days (95% CI 79-NA). Conclusions: The oral outpatient combination of CYT-0851 and cape has demonstrated an acceptable safety and tolerability profile without any unanticipated toxicities at clinically active doses. The disease control rate of 91% and unconfirmed response rate of 27% in refractory platinum resistant ovarian cancer is promising and warrants further exploration. Furthermore, this regimen should be evaluated in other tumor types commonly treated with 5-FU, including breast and colorectal cancer. Citation Format: Elizabeth Swisher, Gerald Steven Falchook, Pamela N. Munster, Nina Beri, Kathleen N. Moore, Timothy A. Yap, David R. Spigel, Susan Doleman, William D. Bradley, Thomas J. O'Shea, Markus F. Renschler, Ryan C. Lynch. Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A13.

Abstract C008: Phase I biomarker analysis of farletuzumab ecteribulin (FZEC), formerly MORAb-202, effects on cancer responses in patients with platinum resistant ovarian cancer

Abstract Background: FZEC (formerly MORAb-202) is an antibody-drug conjugate consisting of farletuzumab and eribulin. FZEC is cytotoxic to FRα+ cancer cells (via direct binding) and to adjacent tumor cells (via bystander effects); it also exerts noncytotoxic bystander effects in the tumor microenvironment (Zhang et al, EORTC 2022). Study 101 is a first-in-human dose escalation followed by dose expansion study in Japanese patients (pts) with selected solid tumors to determine safety and preliminary efficacy of FZEC; antitumor activity across several doses was demonstrated in pts with platinum-resistant ovarian cancer (PROC) and FRα+ tumors (Nishio ASCO 2022). This exploratory biomarker study evaluated association of FZEC-induced pharmacological effects and clinical responses in pts with PROC to examine the mechanism of action (MoA) of FZEC. Methods: Serum samples from up to 58 pts with PROC from a FZEC 0.9 mg/kg cohort (equivalent to 33 mg/m2) or from a combined dose cohort (FZEC 0.3, 0.45, 0.68, 0.9, 1.2 mg/kg) were collected predose on day 1 of treatment cycles 1–6 and analyzed using 139 exploratory Luminex, Simoa, or OLINK protein assays. While these doses are no longer being evaluated, as a result of a change to body-surface-area-based dosing, the biomarkers observed to be preliminarily associated with response in this analysis should be further explored in ongoing studies. Markers with &amp;gt;30% unevaluable data points were excluded. The 1-sample Wilcoxon signed-rank test and 2-sample Wilcoxon rank-sum test were used to assess changes from baseline and differences between 2 best overall response groups (responders [CR/PR] and nonresponders [SD/PD]) at each visit. Fisher’s method was used to summarize statistical difference across visits (meta P&amp;lt;0.05) between the 2 groups. Results: Changes from baseline to at least 1 visit postdose (P&amp;lt;0.05) in either the responder or nonresponder groups, and differences between responders and nonresponders (meta P&amp;lt;0.05), were seen in 29 markers in the combined-dose cohort, and in 14 markers in the 0.9 mg/kg cohort. There was an overlap of 11 markers in both the FZEC 0.9 mg/kg and combined-dose cohorts that showed a significant change from baseline and significant differences in changes between responders and nonresponders. Among these 11 markers, SP-D and IGFBP-2 showed persistent changes (≥3 visits) in responders. Decreases in markers with reported protumor functions (eg, ANG-2, KLK-5, KLK-7, MCP-1, FRTN, and MMP-12), and increases in SP-D, were persistent (≥4 of 5 visits) in responders. Some biomarkers (eg, IGFBP-1, FLT3LG, and VEGF-D) showed significant increases in nonresponders. Conclusions: The persistent responder-associated biomarker changes suggest that FZEC may modulate functions associated with these markers (eg, immune regulation, vascular remodeling, extracellular matrix protease activities, iron metabolism) and this may contribute to the antitumor effect of FZEC. In the limited number of pts analyzed, preliminary pharmacodynamic effects trended with the antitumor effects observed with FZEC 0.9 mg/kg. Citation Format: Yan Zhang, Bob Zimmermann, Shuyu Li, Toshimitsu Uenaka, Keiji Furuuchi, Kan Yonemori, Toshio Shimizu, Shin Nishio, Mayu Yunokawa, Koji Matsumoto, Kazuhiro Takehara, Kosei Hasegawa, Yasuyuki Hirashima, Hidenori Kato, Yohei Otake, Takuma Miura, Junji Matsui, Meijuan Li. Phase I biomarker analysis of farletuzumab ecteribulin (FZEC), formerly MORAb-202, effects on cancer responses in patients with platinum resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C008.

126P Evaluation of myeloid targeting agents, PY159 and PY314, in two dose expansion phase Ib trials in platinum-resistant ovarian cancer

126P Evaluation of myeloid targeting agents, PY159 and PY314, in two dose expansion phase Ib trials in platinum-resistant ovarian cancer