Floriana Camarda

Gut microbiota and its influence on ovarian cancer carcinogenesis, anticancer therapy and surgical treatment: A literature review

Ovarian cancer (OC) is the most lethal gynecological malignancy and very little is known about the underlying tumorigenesis mechanisms. For other tumors, like colorectal cancer, a relationship between several opportunistic pathogens and cancer development and progression has been proven. Recent researches also underline a possible correlation between gut microbiota dysbiosis and cancer treatment efficacy and adverse effects. Several studies have also demonstrated a link between abdominal surgery and gut microbiota modifications. In this paper, we aim to review the available evidences of this issue in OC to understand if there is a relationship between gut microbiota modifications and efficacy and adverse effects of cancer therapies, either surgical and medical treatments. Well-designed clinical studies, with a robust translational component, are required to better understand the modulation of gut microbiota during OC treatment. The microbiota/microbiome composition analysis, in the near future, could represent a novel instrument to personalize anticancer therapies.

Single-cell transcriptome analysis of patient-derived organoids captures inter- and intratumor heterogeneity and uncovers targetable pathways in high grade serous ovarian cancer

High grade serous ovarian cancer (HGSOC) is the most aggressive subtype of ovarian cancer. HGSOC is characterized by high inter- and intra-tumoral heterogeneity, which contributes to chemotherapy resistance. Patient-derived organoids (PDOs) are valuable preclinical models to elucidate the biology of human cancers and to test their response to treatments. This study aims at characterizing the cellular heterogeneity of PDOs and to uncover vulnerabilities of chemotherapy resistant HGSOC. Single-cell transcriptomics of PDOs developed from biopsies of platinum-resistant and platinum-sensitive HGSOC. Chemotherapeutic treatments of HGSOC PDOs and of ascitic-derived ovarian cancer cells and immunohistochemistry analyses of tissues from independent HGSOC patients. HGSOC PDOs comprise subclusters of cells exhibiting different transcriptional states and patient-specific signatures. Proliferative and non-proliferative subclusters co-exist in PDOs and their relative proportion is altered by chemotherapy. Proliferative cell sub-populations exhibit expression of cell cycle and DNA damage response related genes, whereas non-proliferative sub-populations display inflammatory signatures. Furthermore, sensitivity to platinum-based treatments was inversely correlated with oxidative phosphorylation (OXHPOS) in PDOs, indicating a metabolic switch associated with chemoresistance. Accordingly, platinum-resistant PDOs and ascitic HGSOC cells show higher sensitivity to OXHPOS inhibition. We found that neoadjuvant chemotherapy (NACT) directly up-regulates oncogenic and metabolic pathways that are involved in development of recurrence, such as the MYC and OXPHOS genes. NACT also induces the expression of major histocompatibility complex type II (MHC-II) molecules. Immunohistochemistry confirmed MHC-II up-regulation in post-NACT biopsies, indicating that tumour cells mount a general antigen-presenting response upon chemotherapy, associated with recruitment of infiltrating immune cells. PDOs maintain the inter- and intra-tumoral cellular heterogeneity of HGSOC. Chemotherapy targets proliferative cell subclusters, sparing non-proliferative ones. Dependency on OXPHOS represents an actionable vulnerability in PDOs, which can be exploited to hijack chemoresistance. Sequential chemotherapy and immunotherapy may also improve clinical response of HGSOC patients.

Gene actionability according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) in No Specific Molecular Profile (NSMP) endometrial cancer

The No Specific Molecular Profile (NSMP) subtype accounts for ∼30%-40% of endometrial cancer (EC), comprising a heterogeneous group of EC. The primary outcome of this study was the prevalence of actionable genomic alterations in NSMP EC, classified according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Oncogenic and likely oncogenic alterations, pathways, and co-mutation patterns were reported. The analysis was stratified by risk group according to the European Society of Gynaecological Oncology (ESGO)-ESMO-European SocieTy for Radiotherapy and Oncology (ESTRO) guidelines. Patients with NSMP EC enrolled in the FPG500 comprehensive cancer genome profiling program (NCT06020625) were included. Two hundred and fifty-three patients with NSMP EC of any International Federation of Gynecology and Obstetrics (FIGO) stage were enrolled between 1 January 2022 and 31 December 2023. Median age was 62 years, and the most frequent histotype was endometrioid (97%). Ninety-five percent of patients were estrogen receptor positive. Two hundred and thirty-three patients (92%) had at least one ESCAT tier I-III alteration. The most frequent variants were in PTEN [88%, 95% confidence interval (CI) 84% to 92%], PIK3CA (42%, 95% CI 36% to 49%), FGFR2 (15%, 95% CI 11% to 20%), and AKT1 (6%, 95% CI 3% to 10%); 4% (95% CI 2% to 8%) of patients had an ESR1 variant, while KRAS G12C was found in 3% (95% CI 1% to 6%) of patients. The majority of PTEN variants were on the R130 hotspot. More frequent PIK3CA hotspot variants were H1047R (9%), E545D/K/Q/A (6%), and E542K (4%). In the overall population, PIK3CA with PIK3R1 (odds ratio [OR] = 0.07, P value = 4.25 × 10 Our findings highlight potentially actionable alterations in NSMP EC patients, supporting the exploration of tailored molecular-matched therapies according to risk groups.