Recurrent High Grade Serous Ovarian Cancer Management

Luyckx, Mathieu; Squifflet, Jean-Luc; Bruger, Annika M.; Baurain, Jean‐François

doi:10.36255/exon-publications-ovarian-cancer-management

Cited by 6 publications

(2 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite initially responding to chemotherapy, 20% of HGSOC patients relapse within 6 months after completing primary chemotherapy treatment, while 60% of the patients relapse after 6 months ( 50 ). Patients who relapse after a treatment-free interval of more than six months often receive additional carboplatin or paclitaxel-based chemotherapy ( 51 ).…”

Section: Resultsmentioning

confidence: 99%

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

Coelho,

Seashore-Ludlow,

Schütz

et al. 2024

Preprint

View full text Add to dashboard Cite

Resistance to chemotherapy and PARPi inhibitors remains a critical challenge in the treatment of epithelial ovarian cancer, mainly due to disabled apoptotic responses in tumor cells. Given mesothelin's pivotal role in ovarian cancer and its restricted expression in healthy tissues, we conducted a drug-screening discovery analysis across a range of genetically modified cancer cells to unveil mesothelin's therapeutic impact. We observed enhanced cell death in low mesothelin expressing cancer cells when exposed to a second mitochondria-derived activator of caspases (SMAC) mimetics, and demonstrated a compelling synergy when combined with chemotherapy in ex vivo patient-derived cultures and zebrafish tumor xenografts. Mechanistically, the addition of the SMAC mimetics drug birinapant to either carboplatin or paclitaxel triggered the activation of the Caspase 8-dependent apoptotic program facilitated by TNF alpha signaling. Multimodal analysis of neoadjuvant-treated patient samples further revealed an association between tumor-associated macrophages and the activation of TNF alpha-related pathways. Our proposed bimodal treatment shows promise in enhancing the clinical management of patients by harnessing the potential of SMAC mimetics alongside conventional chemotherapy.

show abstract

Section: Resultsmentioning

confidence: 99%

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

Coelho,

Seashore-Ludlow,

Schütz

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Despite the fact that ICI immunotherapy is not as effective as in other solid malignancies (with the response rate to monotherapy in OC patients totaling 10–15%) [ 46 , 47 ], the clinical trials that are currently being conducted determine its impact in monotherapy and/or in combination with other agents, such as biological drugs or standard therapy, to improve OC patients’ outcomes [ 48 , 49 ]. The modes of action of selected ICPs and ICIs are presented in Figure 1 .…”

Section: Treatment Of Ovarian Cancermentioning

confidence: 99%

Current Understanding on Why Ovarian Cancer Is Resistant to Immune Checkpoint Inhibitors

Pawłowska

Rekowska

Kuryło

et al. 2023

IJMS

View full text Add to dashboard Cite

The standard treatment of ovarian cancer (OC) patients, including debulking surgery and first-line chemotherapy, is unsatisfactory because of recurrent episodes in the majority (~70%) of patients with advanced OC. Clinical trials have shown only a modest (10–15%) response of OC individuals to treatment based on immune checkpoint inhibitors (ICIs). The resistance of OC to therapy is caused by various factors, including OC heterogeneity, low density of tumor-infiltrating lymphocytes (TILs), non-cellular and cellular interactions in the tumor microenvironment (TME), as well as a network of microRNA regulating immune checkpoint pathways. Moreover, ICIs are the most efficient in tumors that are marked by high microsatellite instability and high tumor mutation burden, which is rare among OC patients. The great challenge in ICI implementation is connected with distinguishing hyper-, pseudo-, and real progression of the disease. The understanding of the immunological, molecular, and genetic mechanisms of OC resistance is crucial to selecting the group of OC individuals in whom personalized treatment would be beneficial. In this review, we summarize current knowledge about the selected factors inducing OC resistance and discuss the future directions of ICI-based immunotherapy development for OC patients.

show abstract

Dysregulated Cholesterol Metabolism with Anomalous PI3K/Akt/mTOR pathway Predicts Poor Carboplatin Response in High Grade Serous Ovarian Cancer

Mahapatra,

Saha,

Nag

et al. 2024

Preprint

View full text Add to dashboard Cite

Rapidly escalating High-Grade Serous Ovarian Cancer (HGSOC) incidences, relapse, and mortalities result from failed carboplatin therapy. In this regard, reprogrammed cholesterol metabolism arising from deregulated PI3K/Akt/mTOR signaling aggravates HGSOCs to evade carboplatin. Therefore, we designed a pilot study to ascertain their clinical relevance in determining the carboplatin response of HGSOC tumors. Non-NACT HGSOC (n=31) subjects were classified into optimum, borderline, and high cohorts based on blood cholesterol levels which positively correlated with their relative tissue cholesterol content. TCGA database showed that mutations in specific PI3K/Akt/mTOR candidates including cholesterol metabolism regulators (SREBP1, SREBP2, SRB-1, STAR, HMGCR) and prosurvival effectors (Akt, mTOR, p70S6K, P38MAPK, HIF-1α, COX2, VEGF) are characteristic to HGSOCs. We discerned dysregulations (expressions/activity) in SREBP2, SRB-1, STAR, and HMGCR along with Akt/pAktThr308, mTOR/pmTORSer2448, p70S6K, P38MAPK, HIF-1α, COX2, and VEGF proteins within high cohort. Herein, poorly differentiated tumors with escalated HMGCR activity overproduced cholesterol thereby rigidifying their cell membranes to restrain Pt-DNA adduct retention. With a carboplatin IC50 of 5.23μM, high cohort tumors generated lesser drug-induced ROS and espoused unaltered mitochondrial-membrane depolarization and DNA damage profiles. These parameters were moderately altered in the borderline-HGSOC cohort possessing relatively less rigid membranes and a lower carboplatin IC50 of 2.78μM. Accordingly, borderline and high cohorts were respectively denoted as intermediate responder and non-responder of carboplatin. On the contrary, the cholesterol-deficient optimum cohort (IC50-1.59μM) with fluid membranes was a carboplatin responder group. Our study established the candidature of abnormal cholesterol and PI3K/Akt/mTOR (protein-level) statuses as predictive markers to screen HGSOCs for carboplatin responses before therapy.

show abstract

Recurrent High Grade Serous Ovarian Cancer Management

Cited by 6 publications

References 73 publications

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

Current Understanding on Why Ovarian Cancer Is Resistant to Immune Checkpoint Inhibitors

Dysregulated Cholesterol Metabolism with Anomalous PI3K/Akt/mTOR pathway Predicts Poor Carboplatin Response in High Grade Serous Ovarian Cancer

Contact Info

Product

Resources

About