NIH grant: Dual Targeting of Oncogenic Signaling and Immune Suppression in High-Risk T-ALL (1R01CA317674-01)

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NIH grant 1R01CA317674-01: Dual Targeting of Oncogenic Signaling and Immune Suppression in High-Risk T-ALL
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Rosa  Lapalombella. Award: $511944.
Start: 2026-07-16T00:00:00.
ABSTRACT
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10–15% of pediatric and up to 25% of
adult ALL cases. Despite advances in leukemia treatment, adult T-ALL patients continue to face
poor outcomes, with overall survival rates below 50%. Notably, Early T-cell Precursor (ETP)-ALL
represents a particularly aggressive subtype with an especially poor prognosis. There has been
little improvement in mortality or expansion of effective therapeutic options for T-ALL, even amidst
recent progress in precision medicine and immunotherapy. Therefore, identifying novel
'druggable' molecular markers and developing new targeted therapies and combined therapies
are immediate pressing issues in T-ALL. To address this unmet need, we have identified a novel
signaling pathway involving ATAD2, regulated by the CK2/IKAROS axis, which plays a critical role
in T-ALL cell cycle progression. Our preliminary data show that dual targeting of ATAD2 signaling
and the CK2/IKAROS axis results in synergistic anti-leukemic effects in both in vitro and in vivo
models. Furthermore, single-cell RNA sequencing (scRNA-seq) analysis of T-ALL patient samples
revealed significant alterations in the tumor microenvironment (TME). Specifically, we observed
selective expression of the immunomodulatory protein CD70 in malignant TALL cells, along with
enrichment of tumor-associated macrophages (TAMs) and exhausted T cells at diagnosis
compared to remission. Importantly, both the CK2/IKAROS axis and ATAD2 were found to directly
regulate CD70 transcription. Based on these findings, we hypothesize that 1) inhibition of ATAD2
or CD70 can restore antitumor immunity and suppress leukemic progression by
reprogramming the immunosuppressive TME in T-ALL; 2) targeting the CK2/IKAROS axis
may enhance the efficacy of ATAD2 inhibitors and CD70-targeted therapies. To test the
hypothesis, we will examine the anti-leukemic effects and TME remodeling induced by targeting
ATAD2 or CD70 in vitro in high-risk T-ALL patient-derived samples, and in vivo in the DN3 murine
T-ALL and the CEM human T-ALL xenograft models (Aim 1); we will also define the transcriptional
regulation of ATAD2 and CD70 by IKAROS, and assess how CK2 inhibition via CX-4945
modulates their expression and reshapes the TME. We will also evaluate the potential of
CK2/IKAROS axis inhibition to enhance the efficacy of ATAD2 inhibitors and CD70-directed
immunotherapies in vitro and in vivo, including in patient-derived xenograft (PDX) models of highrisk
T-ALL and ETP-ALL (Aim2). This study will provide mechanistic insight into the regulation
and function of ATAD2 and CD70 in high-risk T-ALL and clarify the role of CK2/IKAROS signaling
in their transcriptional control. We expect that single-agent targeting of ATAD2 or CD70 will yield
measurable antileukemic activity, while combination therapy with CK2 inhibition will offer superior
therapeutic benefit by concurrently suppressing gene expression and protein function. Ultimately,
our findings may pave the way for a novel, mechanism-based combination therapy for high-risk
T-ALL, particularly in patients harboring IKZF1 mutations, providing a strong foundation for future
clinical translation. Also, because the complex, systemic immune cells and tumor cells interactions
in the TME of T-ALL cannot be fully replicated in vitro or by computational models, the use of
murine and PDX models is essential. Using these models allows us to evaluate cancer biology,
underlying mechanisms, and systemic efficacy and safety before progressing to human clinical
trials ultimately.

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