Molecular genetic examination revealed a heterozygous pathogenic variant p.Arg1003Ter in the DICER1 gene (NM_030621.4). The presented case emphasizes the importance of molecular genetic diagnosis of DICER1 syndrome in a diagnostic algorithm in the management of patients with TFND and history of malignancy. Considering ERMS of genital tract as a probable component of DICER1 syndrome it is necessary to screen for other manifestations of the disease as well.

The results suggest that treatment of castrate-resistant prostate cancer by imipridones may not be substantially affected by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer.

We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with ONC201 analogue ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis and esophagitis following high doses of thoracic radiation exposure has important translational implications.

We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212.

Imipridones are a promising strategy for further testing and development in mUM.

Moreover, inhibition of caspase-9 activity unexpectedly augmented, rather than attenuated, caspase-3 activation and the subsequent cell death. Collectively, our research identifies ONC212 as an atypical mitochondrial-independent, yet Bcl-2/Bcl-xL-inhibitable, caspase-3-mediated apoptotic cell death inducer, highlighting its potential for combination therapies in tumors with defective mitochondrial apoptotic signaling.

The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer.

The mechanism of impairment of ONC201/206/212 effect caused by dopamine pre-treatment appears to involve upregulation of anti-apoptotic p-Bad, XIAP, FLIP and pAkt. Our results shed light on mechanisms of cancer cell protection by dopamine after imipridone treatment, heterogeneity among different tumor cell types, and suggest that effects of dopamine adaptation on tumor cells may impact on cell survival pathways in ways that may or may not depend on expression of dopamine receptors.

The continuous treatment of U937 cells with the benzene metabolite hydroquinone (HQ) generated U937/HQ cells, exhibiting enhanced responsiveness to the cytotoxic effects of ONC212...Collectively, our data suggested that ONC212 upregulated SLC35F2 expression and triggered NOXA-mediated MCL1 degradation in U937, U937/HQ, and HL-60 cells by activating the AKT/NOX4/HuR/ATF4 pathway. The ONC212-induced signaling pathway showed anti-AML activity and enhanced YM155 cytotoxicity.

We demonstrate that GPX4 inhibition with doxycycline-inducible shRNA or the specific inhibitor ML210 induces ferroptosis in leukemia cells, evidenced by iron-dependent lipid peroxidation and blockade of cell death by the iron chelator deferoxamine. Of note, the classical ferroptosis inducers (xCT inhibitors) sulfasalazine and sorafenib did not induce ferroptosis in AML cells, suggesting a specific relevance of GPX4 in AML ferroptosis...Consistently, degradation of the respiratory complex with hyperactivation of mito-protease ClpP by imipridone ONC212 sensitized cells to GPX4 inhibition in HL60 parental cells but not in rho0 cells, further supporting the role of mito-respiration in the protection of cells against ferroptosis. As venetoclax (Ven) is one of the most widely used mitochondria-targeting agents in AML that also inhibits mito-respiration, we tested the combination of GPX4 inhibitor ML210 and Ven...Unexpectedly, and as a novel mechanism of GPX4 inhibition-mediated ferroptosis, we found that ML210 induces BAX/BAK-independent cytochrome C release from mitochondria, which is blocked by MitoQ... Our data suggest therapeutic potential of ferroptosis induction in AML by targeting GPX4 with the mechanistic involvement of mito-respiration. The combination of GPX4 and BCL-2 inhibition is synergistic and capable of overcoming Ven resistance. Studies are in progress to elucidate the molecular link between mito-respiration/redox and cytochrome C release and to investigate ferroptosis induction in vivo.