Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers

Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12–15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD+) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers

Contribution of Aging, Obesity, and Microbiota on Tumor Immunotherapy Efficacy and Toxicity

Cancer immunotherapy has entered the forefront of cancer treatment, but major challenges still exist, such as the limited proportion of patients that respond to treatment and treatment-related toxicity. Therefore, biomarkers to predict which patients will benefit from therapy without major side effects are of the utmost importance. Moreover, novel therapeutic targets to increase the proportion of responding patients on a given immunotherapy or to alleviate immunotherapy-induced toxicity could be a valuable adjunct to immunotherapy treatment. Host factors such as age, obesity, and the composition of the gut microbiome have considerable effects on immune responses and, hence, could have a large impact on the outcome of immunotherapies. Moreover, since these host factors differ considerably between preclinical mouse models and human cancer patients, it might be possible that these host factors account, in part, for the observed discrepancies in outcomes between mice experiments and clinical trials. In this review, we discuss the latest data on the influence of aging, obesity, and the gut microbiome on the anti-tumor immune response and immunotherapy and propose avenues to increase our knowledge on this topic in order to improve patient selection for cancer immunotherapy treatment.status: publishe

2022-RA-638-ESGO Pembrolizumab with multimodal immunomodulation in chemotherapy-pretreated cervical, endometrial, and uterine cancer: the PRIMMO phase II trial

Introduction/Background To decrease immunosuppression and enhance T-cell activation in the tumour microenvironment, we conducted an open-label, investigator-initiated, multicohort, phase II trial (NCT03192059) of pembrolizumab with multimodal immunomodulation. Methodology Chemotherapy-pretreated patients were recruited into two experimental cohorts (cervical carcinoma or endometrial carcinoma) and one exploratory cohort (uterine sarcoma). Patients received an immunomodulatory five-drug cocktail consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting two weeks before radioimmunotherapy (figure 1). Pembrolizumab, 200 mg/dose, was administered on day 1 of each 21-day cycle from day 15 onwards; one of the tumour lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was objective response rate (irORR) per immune-related response criteria (irRC) at week 26; a lower bound of its 90% confidence interval (CI) of >10% in either experimental cohort was considered successful. Results Fifty patients were enrolled and treated across the cohorts (cervical, n=18; endometrial, n=25; sarcoma=7). Pathology review revealed that 3/7 sarcoma patients had carcinosarcoma. At week 26, the irORR was 11.1% (90%CI, 2.0 to 31.0) in cervical cancer, 12.0% (90%CI, 3.4 to 28.2) in endometrial cancer, and 14.3% (90% CI, 0.7 to 52.1) in uterine (carcino)sarcoma. The best overall response rate per RECIST v1.1 was 22.2% (90%CI, 8.0 to 43.9), 12.0% (90%CI, 3.4 to 28.2), and 28.6 (90%CI, 5.3 to 65.9). Median PFS was 13.4 weeks (11.3 to 26.1), 13.1 weeks (13.1 to 19.4), and 34.3 weeks (95%CI, 5.6 to 77.9) (figure 2A-C). Grade≥3 treatment-related adverse events were reported in 10 (55.6%), 9 (36.0%), and 4 (57.1%) patients. Overall, there was one (2.0%) possible treatment-related death. Health-related quality of life was generally stable over time. Multi-parameter immune monitoring characterised the patients and revealed changes throughout study treatment. Conclusion PRIMMO did not show sufficient evidence of a positive risk-to-benefit ratio to recommend a confirmatory phase III trial

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0–31.0) in cervical cancer and 12.0% (90% CI 3.4–28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1–25.7) in cervical cancer and 3.6 weeks (95% CI 3.6–15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0–67.0) and 37.4 weeks (95% CI 19.0–50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity. Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97)

Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers

Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12–15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD+) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers

Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers

Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12–15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD+) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers