eragidomide (CC-90009)

Here, we applied our recently developed single-cell lineage tracing method ReSisTrace to identify cells that are intrinsically resistant or sensitive to the FLT3 inhibitors midostaurin and quizartinib in AML with FLT3-ITD mutations...In addition, in an FLT3-ITD-positive AML patient-derived xenograft (PDX) mouse model, the CC-90009 and quizartinib combination showed significantly higher anti-tumor efficacy and prolonged overall survival compared to either treatment alone...Vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to sensitize FLT3-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the ability of ReSisTrace to unveil pre-existing transcriptional features of treatment vulnerability in hematological cancers and elucidate strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-mutated AML.

These findings suggest a new role of GSPT1 in regulating leukemic transcriptional networks and open a new therapeutic strategy to target leukemic fusion genes in pediatric AML patients.

Importantly, 7d exhibits superior efficacy compared to 1 (CC-90009) in degrading GSPT1 in 22Rv1 cells with a DC50 value of 19 nM...Mechanistically, via degradation of GSPT1, 7d downregulates CRPC-related oncogenes in 22Rv1 cells, including AR, AR-V7, PSA, and c-Myc. Thus, our work provides a novel GSPT1 selective degrader with potent effectiveness in targeting Myc-driven CRPC.

P1, N=22, Terminated, Celgene | Trial completion date: Oct 2025 --> Apr 2024 | Active, not recruiting --> Terminated; Business objectives have changed.

P1, N=101, Terminated, Celgene | Trial completion date: Jul 2025 --> Apr 2024 | Active, not recruiting --> Terminated; Trial terminated because of lack of efficacy in the short term acute phase.

P1, N=22, Active, not recruiting, Celgene | Phase classification: P1/2 --> P1

P1/2, N=22, Active, not recruiting, Celgene | Phase classification: P1b --> P1/2 | N=76 --> 22

Induction of full-length Rb protein was potentiated by the cereblon E3 ligase modulator CC-90009. These results suggest that pharmacological induction of translational readthrough could be a feasible strategy for therapeutic targeting of tumors with nonsense mutant RB1.

In Phase-1 findings with a selective IRAK4 inhibitor (CA-4948; Curis Therapeutics), it was found that MDS and AML patients with splicing factor mutations responded best to monotherapy IRAK4 inhibition, although the overall response rate with monotherapy was modest...CC-90009 did not result in complete cell death up to concentrations of 10mM in both WT and IRAK4KO, suggesting that the selective sensitivity of IRAK4KO AML cells to CC-885 is not due to inhibition of GSPT1...These findings suggest that IRAK4 inhibition alters the pool of neosubstrates in AML cells for certain CELMoDs. Overall, our study demonstrates that IRAK4 is a therapeutic target in AML, but that combination therapies, such as with certain CELMoDs, will be necessary to achieve better clinical responses.

P1b, N=76, Active, not recruiting, Celgene | Trial completion date: Jan 2025 --> Oct 2025 | Trial primary completion date: Jan 2024 --> Oct 2023

P1b, N=76, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

P1b, N=76, Recruiting, Celgene | N=43 --> 76