SDHC mutation

Herein, we report that SDH-def tumors are sensitive to TMZ, which induces ER stress and upregulates DR5, a pro-apoptotic receptor that can be targeted by INBRX-109 (Figure 1). In turn, TMZ+INBRX-109 additively/synergistically reduces SDH-def GIST cell viability in vitro. These data provide the preclinical evidence for a Phase I clinical trial (3+3 dose escalation design with two dosing cohorts, NCT03715933) to study the safety/tolerability of TMZ+INBRX-109 in patients with aggressive SDH-def cancers, including GIST (Figure 2).

The SDHC c.397C>T mutation is very prevalent in patients with PGLs who are of French Canadian descent due to a likely founder effect. Compared to other SDHC cohorts, SDHC c.397C>T PGLs showed a lower rate of metastasis and associated tumors, but a higher rate of multiple PGLs. Although this may indicate a possibly less aggressive phenotype, the recurrence rate was high at 25%, thus requiring close monitoring and lifelong follow-up.Bibliography:1.

SDHA-mutant patients usually carry two mutational events at the SDHA locus, either the loss of the wild type allele or a second somatic event in compound heterozygosis. This review provides an overview of all data in the literature regarding SDHA-mutated GIST, especially focusing on the prevalence of germline mutations in SDH-deficient GIST populations who harbor SDHA somatic mutations, and offers a view towards understanding the importance of genetic counselling for SDHA-variant carriers and relatives.

Abdominal nonfunctional PGLs are associated with SDHB mutation, and SDHB staining should be performed as a screening.

By developing methods to provide value to rare tumor patients, using a large catchment area and opportunity for remote participation, and collecting data in a tumor-agnostic way, we can learn about multiple rare tumors and share findings more quickly than if each rare tumor was studied alone. We describe the MyPART cohort and challenges to overcome for successful longitudinal rare tumor natural history studies.

However, in our experience, pre-therapy functional imaging with both agents should be performed and used to guide the therapeutic choice as tumors positive with both agents are preferentially treated with I131-MIBG given the FDA label. Additional data is needed for confirmation of these findings.

MGMT promoter hypermethylation occurs exclusively in a subset of dSDH wtGIST. Data from this study support testing of tumour MGMT promoter methylation in patients with dSDH wtGIST to identify those patients who may benefit from most from TMZ therapy.

Treatment with cabergoline, 1.5 mg per week, normalized prolactin in 3 months and stabilized the tumor...This mutation was responsible for jugulo-tympanic paraganglioma, macroprolactinoma, and an RCC. New functional imaging techniques recently developed in vivo (MRI spectroscopy and 68Ga-DOTATOC PET) and in vitro (SDHB immunohistochemistry) allow optimal management of patients with SDHx mutation.

These results suggest that CAFs metabolism impairment was responsible for the decreased invasion process of tumour cells, most likely preventing the release of the pro-migratory factors produced by CAFs. In conclusion, the interplay between CAFs and tumour cells is distinctive depending on the gene involved, and highlights the possibility to inhibit CAF-induced migration by impairing CAFs metabolism, indicating new potential therapeutic scenarios for medical therapy.

Cabergoline treatment may lower elevated 3-methoxytyramine levels and mask the biochemical evidence of metastatic disease. Regular functional imaging with Gallium-68 Dotatate PET/MRI provides better evidence of metastatic disease.

All patients with paragangliomas and pheochromocytomas should ideally be tested for germline mutations in SDH. While there are well identified pathogenic variants associated with hereditary pheochromocytoma and paraganglioma syndromes, with increasing frequency of genetic testing, newer variants in known genetic locations are being identified.