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Sulindac sulfide as a non-immune suppressive gamma-secretase modulator to target Triple-Negative Breast Cancer

ABSTRACT: Triple-negative breast cancer (TNBC) is defined as pathologically negative for estrogen receptor α (ER-), progesterone receptor (PR-), and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy, recently supplemented by immunotherapy [37296893]. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including gamma secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs. We confirmed that SS, a known gamma secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, the anti-tumor effects of SS were significantly enhanced when combined with α-PD1 immunotherapy in our TNBC organoids and in vivo. Our data support further investigation of SS for the treatment of TNBC, in conjunction with standard of care chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option solution for a patient population in need of effective therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE241064 | GEO | 2023/11/21

REPOSITORIES: GEO

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Project description:Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL. Experiment Overall Design: Duplicate samples (biologic replicas) from CUTLL1 cells were treated for 24 hours with vehicle only (DMSO), dexamethasone (1microM), a gamma-secretase inhibitor (CompE 100nM) and a combination of dexamethasome plus gamma secretase inhibitor at the same concentrations indicated before. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (CompE) or the combination of both treatments.

Project description:Somatic NOTCH1 mutations are found in ~60% of T lineage acute lymphoblastic leukemias (T-ALLs). Notch1 is cleaved by γ secretase to generate activated Notch intracellular domain (NICD) proteins. The NOTCH1 mutations found in T-ALL constitutively activate Notch1 signaling by increasing NICD levels. Genetic alterations in components of the Ras/PI3 kinase (PI3K)/Akt pathway are also highly prevalent in T-ALL, and often coexist with NOTCH1 mutations. Exposing a T-ALL cell line to the PI3 kinase (PI3K) inhibitor GDC-0941 generated drug resistant clones that down-regulated NICD expression. To address the in vivo relevance of this unexpected observation, we transplanted primary wild-type (WT) and KrasG12D mutant T-ALLs into recipient mice, and treated them with GDC-0941 alone and in combination with the MEK inhibitor PD0325901 (PD901). Although many leukemias responded dramatically to these targeted agents in vivo, drug-resistant clones invariably emerged. Multiple resistant T-ALLs lost NICD expression through mechanisms that included loss of Notch1 mutations found in the parental T-ALL. These GDC-0941-resistant leukemias exhibited reduced expression of many Notch1 target genes, elevated levels of phosphorylated Akt (pAkt), and displayed cross-resistance to γ secretase inhibitors (GSIs). Consistent with these data, inhibiting Notch1 activity in T-ALL cells enhanced PI3K signaling, providing a likely mechanism for in vivo selection against clones with Notch1 pathway activation. Thus, oncogenic Notch1 mutations that promote clonal outgrowth during malignant transformation unexpectedly “switch” to become deleterious during treatment with a PI3K inhibitor. These data advance our understanding of T-ALL pathogenesis and have implications for implementing new therapeutic regimens. We analyzed 28 mouse T-ALL samples obtained after in vivo treatment with GDC-0941 alone or GDC-0941 + PD0325901. These T-ALL samples are either Kras wild type or harbor a KrasG12D mutations.

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Sulindac sulfide as a non-immune suppressive gamma-secretase modulator to target Triple-Negative Breast Cancer

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