T Acute Lymphoblastic Leukemia

P2, N=90, Not yet recruiting, SWOG Cancer Research Network

P=N/A, N=148, Completed, The Children's Hospital of Zhejiang University School of Medicine | N=69 --> 148 | Trial completion date: Dec 2022 --> Dec 2025

Interestingly, aCD7P-VCR treatment substantially reduced leukemia progression and invasion in the orthotopic CCRF-CEM T-ALL model without toxic effects, leading to significantly longer survival than clinically used VCR and nontargeted P-VCR. aCD7P-VCR is expected to provide an effective and targeted therapeutic approach for T-ALL.

By developing and characterizing a unique RiboCancer cell line panel, we mapped translational rewiring driven by the most frequent somatic RP mutations. We provide unprecedented mechanistic insights into translation defects induced by CLL-associated Rps15 mutations, and reveal an intriguing translation-based rewiring of transcription in CLL.

Detection of NOTCH1 JME-ITDs depends strongly on variant-calling strategy. Combining haplotype-based callers with split-read structural variant tools may reduce false negatives and improve detection of clinically relevant insertions in diagnostic NGS pipelines.

Using T-ALL PDXs we further show that (i) ADC-CD7-BCL-XLi displays potent anti-leukemic activity and is devoid of toxicity to platelets; (ii) ADC-CD7-BCL-XLi acts synergistically with venetoclax, a BCL-2 selective antagonist, to prolong leukemia remission and mouse survival; (iii) the anti-leukemic effect of the ADC-CD7-BCL-XLi+venetoclax combination can lead to cure when combined with chemotherapy. These pre-clinical data strongly support the evaluation of ADC-CD7-BCL-XLi in T-ALL patients, including as a potential bridging option to curative hematopoietic stem cell transplantation (HSCT).

Co-treatment with BD-1047 further enhanced Siramesine-induced cell death, apoptosis, and alterations in autophagic signaling. These findings demonstrate that S1R inhibition sensitizes leukemia cells to S2R-mediated cytotoxicity, supporting the therapeutic potential of combined sigma receptor targeting and warranting further investigation of Siramesine-based metronomic therapy in leukemia.

Unlike inhibitors and inhibitor-based PROTACs, these MGDs engage LCK in regions distal to the ATP binding site and thus their activities in T-ALL are not affected by gate-keeper LCK mutations that drive resistance to inhibitor-based therapeutics. Taken together, our data highlights the potential of LCK-targeting MGDs as a strategy to overcome kinase inhibitor resistance in T-ALL, offering a framework for targeting kinase dependencies in drug-refractory hematologic malignancies more broadly.

P1, N=24, Suspended, City of Hope Medical Center | Recruiting --> Suspended

Further cell assay experiments confirmed that cells expressing individual fusion genes were more sensitive to the suggested drugs, and the key downstream genes were affected by our drugs. FusionTarget provides a unique foundation for developing therapeutics targeting fusion proteins.

Among the pharmacogenetic factors influencing toxicity of commonly used B-ALL treatments, variants in the TPMT and NUDT15 genes, both involved in the metabolism of 6-mercaptopurine, represent the most robust and clinically validated predictors. Emerging evidence also links additional genetic variants to toxicities associated with other key agents used in ALL treatment regimens, including variants in SLCO1B1 associated with methotrexate-related gastrointestinal toxicity and variants in CEP72 associated with vincristine-induced neuropathy. The integration of pharmacogenomic biomarkers into clinical protocols, enabling genotype-guided dose adjustment, may represent a valuable strategy to avoid toxicity and improve overall cancer outcomes. However, further studies and innovative approaches are required to validate emerging biomarkers and facilitate their translation into routine clinical practice.

When combined with L-asparaginase, ASX-173 effectively eliminated ASNS-high leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.