This study evaluated the anti-myeloma activity of nuvisertib using in vitro and in vivo preclinical models. Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells within the bone marrow, leading to the production of monoclonal immunoglobulin and progressive marrow failure. Despite significant therapeutic advances, MM remains largely incurable, with many patients eventually relapsing or developing resistance to treatment. PIM-1 is frequently overexpressed in hematologic malignancies and contributes to malignant cell growth and resistance mechanisms. Nuvisertib (TP-3654), an oral PIM-1 kinase inhibitor currently under clinical investigation for myelofibrosis (NCT04176198), may be a potential therapeutic candidate for MM due to its role in modulating cell survival and proliferation pathways, particularly through the JAK/STAT signaling axis. While pan-PIM inhibitors have demonstrated anti-tumor activity in relapsed/refractory MM patients with acceptable tolerability, there are no published preclinical or clinical data on the anti-MM effects of nuvisertib. In this study, in vitro assays were conducted using bone marrow cells from MM patients and human MM LAGλ-1 cells. Cells were treated with nuvisertib alone or in combination with standard MM therapies. Cell viability was assessed using MTS assays after 48 hours of treatment. In vivo efficacy was evaluated in SCID mice implanted with LAGκ-2 or LAGλ-1 MM patient-derived xenografts (PDXs) in the gluteal muscle of the left hind limb. Once tumors became palpable, mice were randomized (n=10 per group) and treated orally with nuvisertib or vehicle control and tumor volumes measured during treatment. After 2–4 weeks, depending on tumor progression, mice were sacrificed and tumors harvested for weight analysis. Nuvisertib demonstrated potent, dose-dependent cytotoxicity in vitro, with an IC30 value of 1.11 µM, comparable to those of established MM drugs including dexamethasone (1.32 µM), cyclophosphamide (1.01 mM), lenalidomide (95.1 µM), and pomalidomide (16.5 µM). When combined with other agents, nuvisertib exhibited additive anti-proliferative effects, particularly in samples from patients with progressive disease (>50% malignant plasma cells). In contrast, samples from patients in complete response (<5% plasma cells) showed less pronounced effects. These findings suggest nuvisertib may be potentially active in drug-resistant or relapsed/refractory MM patients. In vivo, nuvisertib reduced tumor volume in both LAGκ-2 and LAGλ-1 models compared to controls, with final tumor volumes of 1385 mm3 and 2838 mm3 in treated groups versus 2789 mm3 and 6258 mm3 in vehicle groups, respectively (p<0.013). Tumor weights were also lower in nuvisertib-treated mice (p<0.04). These results support nuvisertib as a potential therapeutic agent for MM, both as a monotherapy and in combination with currently used treatments. Further studies using preclinical human MM PDX models are warranted to evaluate drug interactions and impact on overall survival. Zakir Khan, Stacy Behare, Mingjie Li, Jason M. Foulks, Steven L. Warner, James R. Berenson. Nuvisertib shows single-agent anti-tumor activity in multiple myeloma nonclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A098.

BACKGROUND:Tumor-associated macrophages (TAMs) are key promoters of inflammatory breast cancer (IBC), the most aggressive form of breast cancer. The receptor tyrosine kinase AXL is highly expressed in various cancer types, including IBC, but its role in TAMs remains unexplored. METHODS:We examined the effects of AXL inhibitor TP-0903 on tumor growth and tumor microenvironment (TME) component M2 macrophages (CD206+) in IBC and triple-negative breast cancer mouse models using flow cytometry and immunohistochemical staining. Additionally, we knocked out AXL expression in human THP-1 monocytes and evaluated the effect of AXL signaling on immunosuppressive M2 macrophage polarization and IBC cell growth and migration. We then investigated the underlying mechanisms through RNA sequencing analysis. Last, we performed CIBERSORT deconvolution to analyze the association between AXL expression and tumor-infiltrating immune cell types in tumor samples from the Inflammatory Breast Cancer International Consortium. RESULTS:We found that inhibiting the AXL pathway significantly reduced IBC tumor growth and decreased CD206+ macrophage populations within tumors. Mechanistically, our in vitro data showed that AXL promoted M2 macrophage polarization and enhanced the secretion of immunosuppressive chemokines, including CCL20, CCL26, and epiregulin, via the transcription factor STAT6 and thereby accelerated IBC cell growth and migration. RNA sequencing analysis further indicated that AXL signaling in immunosuppressive M2 macrophages regulated the expression of molecules and cytokines, contributing to an immunosuppressive TME in IBC. Moreover, high AXL expression was correlated with larger populations of immunosuppressive immune cells but smaller populations of immunoactive immune cells in tissues from patients with IBC. CONCLUSIONS:AXL signaling promotes IBC growth by inducing M2 macrophage polarization and driving the secretion of immunosuppressive molecules and cytokines via STAT6 signaling, thereby contributing to an immunosuppressive TME. Collectively, these findings highlight the potential of targeting AXL signaling as a novel therapeutic approach for IBC that warrants further investigation in clinical trials.

Checkpoint kinase 1 (CHK1) plays a critical role in DNA damage repair by responding to and managing DNA replication stress. CHK1 activation results in cell cycle arrest and the induction of DNA damage repair pathways. Targeting CHK1 is a promising therapeutic strategy due to high levels of replication stress in cancer cells. CHK1 inhibition causes replication catastrophe and inhibits cell growth in a wide range of cancers (Toledo L, 2017). In the past decade, multiple drugs targeting this pathway have been tested in clinical trials (de Costa AABA, 2023). Although some of the CHK1 inhibitors showed promising clinical responses as monotherapies or in combination therapies in patients with gynecological cancers, efficacies were limited due to toxicities. To maximize the potential for efficacy and limited toxicities, we utilized a CHK1 inhibitor formulated as a liposomal nanomedicine since liposomal drugs are reported to alter drug distribution to achieve longer drug retention in plasma and higher accumulation in tumors in preclinical and clinical settings (J Vaage, 1997, Barenholz Y, 2012, Northfelt DW, 1996). SMP-3124 is an investigational selective CHK1 inhibitor encapsulated within a liposome. SMP-3124 showed a durable pharmacodynamic response due to the liposomal accumulation in the tumor in an ES-2 ovarian cancer xenograft model. We confirmed potent anti-tumor activities of SMP-3124 in multiple preclinical subcutaneous xenograft models without weight loss. To further evaluate the potential of SMP-3124, especially in recurrent ovarian cancer, we established a novel preclinical model from the ascites of a patient with multiple treatment-resistant ovarian cancers. The preclinical study using this model revealed resistance to the standard treatment drugs in ovarian cancer, while showing sensitivity to SMP-3124. Furthermore, we investigated the therapeutic potential of SMP-3124 in patient-derived xenograft models of ovarian cancer, including platinum-resistant models generated at Kyoto University. SMP-3124 showed more than 40% tumor regression relative to baseline in seven out of fourteen of the preclinical patient-derived xenograft models and achieved complete remission in three cases. These results support the investigation of SMP-3124 in ovarian cancer patients and the ongoing phase 1/2 study of SMP-3124 in adults with advanced solid tumors overall. Yuka Kumagai, Junzo Hamanishi, Ryusuke Murakami, Kana Shimizu, Yosuke Ota, Yusuke Sawayama, Naoaki Shimada, Kento Hayashi, Yoshiko Fukuoka, Steven L. Warner, Jason M. Foulks, Masaki Mandai, Makoto Matsuoka, Seiji Kamioka, Hitoshi Ban, Hiroki Umehara. Evaluation of SMP-3124, a novel liposome-encapsulated CHK1 inhibitor, in patient-derived preclinical models of treatment-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2903.

We identified activin A receptor type I (ACVR1), a member of the TGF-β superfamily, as a factor favoring acute myeloid leukemia (AML) growth and a new potential therapeutic target. ACVR1 is overexpressed in FLT3-mutated AML and inhibition of ACVR1 expression sensitized AML cells to FLT3 inhibitors. We developed a novel ACVR1 inhibitor, TP-0184, which selectively caused growth arrest in FLT3-mutated AML cell lines. Molecular docking and in vitro kinase assays revealed that TP-0184 binds to both ACVR1 and FLT3 with high affinity and inhibits FLT3/ACVR1 downstream signaling. Treatment with TP-0184 or in combination with BCL2 inhibitor, venetoclax dramatically inhibited leukemia growth in FLT3-mutated AML cell lines and patient-derived xenograft models in a dose-dependent manner. These findings suggest that ACVR1 is a novel biomarker and plays a role in AML resistance to FLT3 inhibitors and that FLT3/ACVR1 dual inhibitor TP-0184 is a novel potential therapeutic tool for AML with FLT3 mutations.

BackgroundSuicide is a leading cause of death among service members and veterans. Among suicide methods, firearms are the most lethal and commonly used method among military populations. Limited research has compared risk factors for the various suicide methods. This study evaluated and compared risk factors for firearm versus non-firearm suicides using data from the Millennium Cohort Study, a large longitudinal military cohort.MethodsUsing a competing risk approach, we identified factors associated with each suicide method. Risk factors included demographics, mental health diagnoses, mental health symptoms, military-specific characteristics, health behaviors, and psychosocial factors. Cause of death was assessed from July 1, 2001, through December 31, 2018.FindingsAmong 201,565 eligible participants with a mean [SD] age of 29.0 [58.1] years, there were 139,789 (69.3%) male, 61,776 (30.7%) female, 15,927 (7.9%) Hispanic, 24,667 (12.3%) non-Hispanic Black, 14,138 (7.0%) Asian, Pacific Islander, American Indian or Multiracial, and 146,736 (72.8%) non-Hispanic White participants. During the study period, 330 died by firearm suicide and 168 died by non-firearm suicide. Overall, effect estimates for risk factors were similar across both methods of suicide. After adjustment, men (HR: 3.69, 95% CI: 2.59, 5.24) and those who screened positive for depression (HR: 1.97, 95% CI: 1.36, 2.87) had an elevated risk for firearm suicide. In contrast, those who self-reported a history of bipolar diagnosis (HR: 3.40, 95% CI: 1.76, 6.55) had significantly increased risk for non-firearm suicide.InterpretationFindings suggest that prevention and intervention strategies overall may not need to be differentiated by specific demographic, military, or health factors. Targeted interventions that consider sex and mental health screens might have relative utility in preventing firearm related suicide risk compared with non-firearm suicide.FundingMilitary Operational Medicine Research Program, Defense Health Program, and Department of Veterans Affairs.

PDF file - 27K, SGI-7079 and erlotinib do not adversely affect animal body weight

Introduction: Triple-negative and inflammatory breast cancer (TNBC and IBC) are the most aggressive breast cancer subtypes. Novel actionable targets and complementary therapies are critically needed. AXL, a receptor tyrosine kinase, drives pleiotropic phenotypes of TNBC and IBC aggressiveness. Targeting AXL reduces IBC tumor growth in vivo and inhibits polarization of M2 macrophages. To identify novel tumor microenvironment (TME) targets to enhance the efficacy of AXL-targeted therapy, we conducted a synthetic lethal kinome siRNA screening. We identified TBK1 as a candidate to synergize with AXL growth inhibition. TBK1 is a serine/threonine protein kinase that regulates innate, adaptive responses and antitumor immune responses. We hypothesized that inhibition of TBK1 enhances the antitumor effect of AXL-targeted therapy in aggressive breast cancers. Methods: We used knockdown, knockout (KO) and inhibitors to suppress AXL and TBK1 pathways and tested the synergistic effect of targeting AXL and TBK1 on the growth of human SUM149 and BCX010 IBC cells, and HS578T TNBC cells in vitro. To determine the synergistic effect of targeting both pathways in vivo, we inoculated control or TBK1 KO murine TNBC 4T1.2 cells into BALB/c mice. We assessed the activity of AXL inhibitor TP-0903 in reducing tumor growth. Using multicolor flow cytometry, we studied the effects of targeting AXL and TBK1 on the TME. We tested the activity of TP-0903 combined with a TBK1 inhibitor in another TNBC mouse model, E0771. We used RNA-sequencing and real-time PCR/Western blot to determine the molecular mechanisms of how TBK1 inhibition synergizes AXL-targeted therapy in these cancers. Results: Compared with AXL or TBK1 suppression alone, genomic or pharmacologic suppression of AXL and TBK1 significantly reduced the growth of SUM149, BCX010, and HST578T cells in vitro. In both 4T1.2 and E0771 syngeneic mouse models, TP-0903 was more active in reducing tumor growth in TBK1-inhibited tumors than in control tumors. Tumors with TBK1 inhibition and treated with TP-0903 had a significantly higher population of cytotoxic T cells than control tumors. Depletion of CD8+ T cells blocked the synergistic effect of targeting AXL and TBK1 pathways on reducing tumor growth, suggesting that cytotoxic T cells contributed to the anti-tumor synergy of targeting AXL and TBK1. Mechanistically, TBK1 induced M2 macrophage migration via IRF3-regulated CCL5 secretion in SUM149 and HS578T cells, and AXL KO attenuated the polarization and migration of M2 macrophages by inhibiting the CCR5/CCL5 axis. Conclusions: Targeting TBK1 enhances the efficacy of AXL-targeted therapy in aggressive breast cancer by suppressing the paracrine effect of CCR5/CCL5 axis. This combination represents a novel and effective therapy modulating the TME of aggressive breast cancer, which warrants further investigation in the clinical setting. Citation Format: Lan Phi, Takashi Semba, Ngu V. Trinh, Fang Zou, Jason M. Foulks, Steven L. Warner, Savitri Krishnamurthy, James P. Long, James M. Reuben, Debu Tripathy, Naoto T. Ueno, Xiaoping Wang. TBK1 inhibition potentiates the efficacy of AXL-targeted therapy by modulating tumor microenvironment in aggressive breast cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3635.

Transforming growth factor-β (TGF-β) receptors regulate SMAD signal transduction and a wide-range of biological processes including, wound healing, angiogenesis, immune modulation, epithelial-mesenchymal transition, cell differentiation, apoptosis, growth, and motility. In transformed cells, TGF-β signaling is frequently exploited to reshape the architecture of the tumor microenvironment (TME) and establish a fibrotic barrier that insulates the tumor from surrounding normal tissue. As a result, immunological threats to the tumor are restricted, as is the anti-tumorigenic potential of immunotherapeutic interventions. Clinically, TGF-β hyperactivity is associated with immunotherapy resistance and poor outcome in a variety of malignancies. We hypothesize that TP-6379, an investigational small molecule inhibitor of TGFBR1, may remodel the TME to expand the access of tumor-seeking lymphocytes to tumor tissue. Herein we describe several anti-tumorigenic effects of TP-6379 observed in multiple mouse models of cancer both as a single agent, and in combination with immunotherapy. In an EMT6 syngeneic mouse model of triple-negative breast cancer (TNBC), we observed that tumor phospho-SMAD2/3 (pSMAD2/3) levels quickly declined post-TP-6379-treatment and were suppressed by 74% after 8 hours. Preclinical data showed TP-6379 plasma levels inversely correlated with pSMAD2/3 suppression. TP-6379 alone was observed to inhibit tumor growth in EMT6 and 4T1 TNBC models, an activity that was enhanced when augmented by immunotherapy. In a Cloudman S91 syngeneic melanoma mouse model, there was a clear subset of mice that responded to combination treatment. Histological analyses of TNBCs and responsive melanomas showed that TP-6379 treatment conferred a loss of induration of tumors, increased vascularization, and increased infiltration of CD45+ leukocytes (including CD8+ T cells), particularly when combined with immunotherapy. High-throughput analyses of tumors uncovered an array of MHC class I and II factors that were observed elevated subject to TP-6379 treatment, an activity that was oftentimes enhanced when combined with immunotherapy. Collectively, these data suggest that TP-6379 may improve immune cell access to tumor tissue via TME remodeling and normalization of vascular networks. Thus, TP-6379 treatment may present a unique and multifactorial anti-tumor strategy, 1) as a single agent to improve anti-tumorigenic immunological responses, and 2) as a combination treatment to boost immunotherapeutic activity. Citation Format: David A. Kircher, Tetyana V. Forostyan, Richard E. Heinz, Curtis A. Allred, Sal Sommakia, Yuta Matsumura, Adam Siddiqui, Jason M. Foulks, Steven L. Warner. TP-6379, an investigational TGFBR1 inhibitor, shown to remodel the tumor microenvironment and enhance anti-tumorigenic immunological responses in syngeneic mouse models of cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5171.

PDF file, 76K, Relation between TIG1 expression status and clinicopathologic factors of the IBC patient tissues.

Supplementary figures show the efficacy of TP-0903 and its effects on tumor infiltrating immune cells and EMT markers expression.

PDF file - 96K, Structure of pyrrolopyrimidine AXL inhibitor SGI-7079

PDF file - 51K, EMT status of commonly mutated genes in NSCLC

Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting "M2-like"phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.

Adult granulosa cell tumor (AGCT) is a subtype of sex-cord stromal tumors and accounts for ~5% of all ovarian neoplasms. Nearly 100% of AGCT cases are caused by an oncogenic point mutation in the Forkhead Box L2 (FOXL2) transcription factor. Weis-Banke et al. found this gain-of-function mutation (FOXL2C134W) allows FOXL2 to hijack the nuclear SMAD2/3/4 complex, the downstream effector of transforming growth factor- ß (TGF-ß), and redirect to novel transcription sites, inducing transcription of epithelial to mesenchymal transition (EMT) and other oncogenes. We hypothesized that FOXL2 mutant AGCT would be sensitive to TGF-ß inhibition. To test this hypothesis, we treated two GCT cell lines with TP-6379, an orally available, investigational small molecule kinase inhibitor of TGFBR1 that has been shown to block the phosphorylation and nuclear translocation of SMAD2 and SMAD3 in cells. TP-6379 was tested in the KGN cell line, derived from an AGCT patient and heterozygous for the FOXL2C134W mutation, and the COV434 cell line, derived from a juvenile GCT patient, which is FOXL2 wild type (WT). KGN cells (IC50 = 135 nM) were observed to be more than 70-fold more sensitive to TP-6379 treatment than COV434 (IC50 = >10,000 nM), after a 6- and 7- day treatment, respectively. KGN cells that were edited to remove the WT FOXL2 or both the WT and FOXL2C134W alleles were observed to be 1.6-fold more sensitive to TP-6379 and 22-fold less sensitive than the parental KGN cells. In vivo testing using KGN cells is ongoing. Viably cryopreserved dissociated tumor cells (DTCs) from two AGCT patients and one JGCT patient, which contain a mixture of tumor, immune, endothelial, and other stromal cells, were also tested in proliferation assays with TP-6379. All three ex vivo samples were positive for the FOXL2C134W mutation as detected by a qPCR genotyping assay and were sensitive to TP-6379 (IC50 = 555-1600 nM) after 6-day treatment. Xenograft models using these patient samples are currently under development. TGF-ß signaling is also a master regulator of the tumor microenvironment (TME) and immune evasion by modulating deposition of extracellular matrix and suppression of immune cells. We performed an immunophenotyping assay in tissue microarrays of thin-needle biopsy cores of multiple cancer types by looking at the distribution of CD8 T cells within tumor and stroma. AGCT showed the strongest excluded and desert phenotype among the tested cancer types, where CD8 T cells were confined to the stroma or absent entirely. TP-6379 treatment was observed to increase expression and reverse TGF-ß induced suppression of HLA class I in KGN cells. These data suggest that TGF-ß may play a significant role in the TME of AGCT. In conclusion, preclinical data shows inhibition of TGFß signaling with TP-6379 in FOXL2C134W mutant AGCT is active at blocking cell growth and may prove to be a potential therapy in this rare disease. Citation Format: Curtis A. Allred, Richard E. Heinz, Yuta Matsumura, Tetyana V. Forostyan, David Kircher, Salah Sommakia, Thomas Welte, Veena Vuttaradhi, Jason M. Foulks, Steven L. Warner, R Tyler Hillman. TGFBR1 as a novel therapeutic target in adult granulosa cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1617.

Background: The inflammaging modulator, S100A9, mediates immunosuppression and plays a key role in the pathogenesis of low-risk myelodysplastic syndrome (MDS). Specifically, S100A9’s feedforward activation in the bone marrow (BM) induces pyroptotic cell death of hematopoietic stem and progenitor cells (HSPC) and the activation and accumulation of myeloid-derived suppressor cells (MDSC). This process creates a suppressive microenvironment including the secretion of transforming growth factor β (TGFβ) that signals through the TGFβ receptor 1 (TGFBR1) to induce inhibitory processes that contribute to this phenotype. We hypothesize that targeting with an investigational TGFBR1 inhibitor, TP-6379, reduces immune suppression and restores hematopoiesis in MDS. Methods: Primary low risk MDS BM mononuclear cells (BMMNC) were obtained from the Moffitt Total Cancer Care Protocol and cultured in vitro with TP-6379. Healthy BMMNC were purchased, treated with or without recombinant S100A9 and TP-6379. Results: Treatment of primary MDS BMMNC (n=15) and S100A9-treated healthy BMMNC (n=5) with TP-6379 for 48 hours was observed to significantly improve proliferation of hematopoietic progenitor cells as measured by colony forming capacity. Total colonies, and BFU-E specific colonies, showed significant increase. This expansion of progenitors with treatment was validated by flow cytometric analysis of Lineage−HLA-DR−CD34+ HSPC and showed a reduction in genomic instability, measured by γH2AX. In addition, TP-6379 was observed to reduce the numbers of suppressive mediators; MDSC, T regs and senescent lymphocytes and increase the number of cytotoxic cells, including NK cells. Our analysis revealed that BMMNC with spliceosomal mutations, including SF3B1, have elevated sensitivity to TP-6379 treatment. Therefore, we tested wild type and SF3B1 K700E CRISPR knock-in K562 cells in the presence of TP-6379 for 48 hours. K562 is a well-established cell line model for study of MDS. The SF3B1 mutant expressing cells have significantly reduced BFU-E colony forming capacity, compared to wild type cells, concordant with higher pyroptosis activation and consistent with the BMMNC results. Hence, we measured phospho-SMAD activity, as a direct measure of TGFBR1 inhibition. SF3B1 mutant expressing cells were shown to be highly sensitive to TP-6379, with a significant loss of SMAD activation. Expression analysis of primary MDS, S100A9-treated healthy BMMNC cells and K562 SF3B1 mutant cells revealed elevated expression of SERPINE1 which was rescued by TP-6379 treatment. Conclusions: TP-6379 restores healthy hematopoiesis in low-risk MDS, which may translate into a strong therapeutic option in a disease with few clinical options. Importantly, our work also suggests a specific role for spliceosome dysfunction in bone marrow failure and a novel role for SERPINE1 in MDS and S100A9-induced suppression. Citation Format: Erika A. Eksioglu, Gabriela M. Wright, Jason M. Foulks, Matthew Lalonde, Steven L. Warner, Kenneth L. Wright. Improvement of hematopoiesis in primary low risk MDS with the TGFBR1 investigational inhibitor TP-6379. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5150.

PDF file - 71K, Percentage tumor volume compared to control, survival and therapeutic efficacy at days 17 and 38 post-treatment

PDF file - 116K, EMT signature predicts erlotinib sensitivity better than CDH1 or VIM probes. IC50 levels for erlotinib are shown

PDF file - 109K, EMT signature predicts resistance to EGFR and PI3K inhibitors and greater sensitivity to Axl inhibition