Sulindac sulfide as a non-immune suppressive γ-secretase modulator to target triple-negative breast cancer
Fokhrul Hossain1, Deniz A Ucar1, Giulia Monticone1
1Department of Genetics, Louisiana State University Health Sciences Center, New Orleans (LSUHSC-NO), New Orleans, LA, United States.
Introduction:
Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy. Despite promising results, the efficacy of immunotherapy and chemo-immunotherapy in TNBC remains limited. 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 g-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.
Methods:
We investigated the pharmacological and immunotherapeutic properties of SS in TNBC models in vitro, ex-vivo and in vivo.
Results:
We confirmed that SS, a known γ-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, SS did not inhibit Notch cleavage in T- cells, and the anti-tumor effects of SS were significantly enhanced when combined with a-PD1 immunotherapy in our TNBC organoids and in vivo.
Discussion:
Our data support further investigation of SS for the treatment of TNBC, in conjunction with chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option for a patient population in need of more effective therapies.
Insights
Sulindac sulfide (SS) shows promise in treating triple-negative breast cancer (TNBC) by inhibiting Notch1 signaling without harming anti-tumor immunity. This FDA-approved drug enhances immunotherapy, offering a potentially cost-effective TNBC treatment option.
Area of Science:
- Oncology
- Cancer Signaling
- Drug Discovery
Background:
- Triple-negative breast cancer (TNBC) is aggressive with limited treatment options, primarily chemotherapy.
- Notch signaling is implicated in TNBC progression, with Notch1 inhibitors showing preclinical efficacy but clinical limitations due to toxicity.
- Current research seeks safer alternatives to Notch inhibitors like g-secretase inhibitors (GSIs) that avoid systemic toxicity and preserve anti-tumor immunity.
Purpose of the Study:
- To investigate the pharmacological and immunotherapeutic potential of sulindac sulfide (SS) as a GSI alternative for TNBC treatment.
- To evaluate SS's efficacy as a single agent and in combination with immunotherapy in preclinical TNBC models.
Main Methods:
- Investigated SS in in vitro, ex vivo, and in vivo TNBC models.
- Assessed SS's effect on Notch1 cleavage, mammosphere growth, and tumor progression.
- Evaluated SS in combination with anti-PD1 immunotherapy in TNBC organoids and mouse models.
Main Results:
- SS, a gamma-secretase modulator, effectively inhibited Notch1 cleavage and mammosphere growth in TNBC cells.
- SS demonstrated significant single-agent anti-tumor activity in a mouse TNBC model, reducing Notch1 expression.
- SS did not impede T-cell Notch cleavage and synergized with anti-PD1 immunotherapy to enhance anti-tumor effects.
Conclusions:
- Sulindac sulfide (SS) is a promising candidate for TNBC treatment, potentially replacing GSIs due to its favorable toxicity profile.
- SS warrants further investigation for TNBC therapy, particularly in combination with chemotherapy or immunotherapy.
- Repurposing FDA-approved SS offers a cost-effective and rapidly deployable therapeutic strategy for TNBC patients.
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