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Targeted SPP1 Inhibition of Tumor-Associated Myeloid Cells Effectively Decreases Tumor Sizes
Benan Kartal1, Christopher S Garris1, Hyung Shik Kim1
1Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA, 02114, USA.
Abstract:
Secreted phosphosprotein 1 (SPP1)High tumor-associated macrophages (TAM) are abundant tumor myeloid cells that are immunosuppressive, pro-tumorigenic, and have a highly negative prognostic factor. Despite this, there is a lack of efficient TAM-specific therapeutics capable of reducing SPP1 expression. Here, on a phenotypic screen is reported to identify small molecule SPP1 modulators in macrophages. Several hits and incorporated them into a TAM-avid systemic nanoformulation are identified. It is shown that the lead compound (CANDI460) can down-regulate SPP1 in vitro and in vivo and lead to tumor remissions in different murine models. These findings are important as they offer a promising avenue for developing novel therapeutic strategies targeting TAM.
Insights
Researchers identified small molecules that reduce SPP1 expression in tumor-associated macrophages (TAMs). The lead compound, CANDI460, demonstrated effectiveness in preclinical models, offering a new therapeutic strategy targeting TAMs for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Secreted phosphoprotein 1 (SPP1)-high tumor-associated macrophages (TAMs) are immunosuppressive myeloid cells associated with poor prognosis in cancer.
- Current therapeutic strategies lack specificity and efficacy in targeting TAMs to reduce SPP1 expression.
Purpose of the Study:
- To identify small molecule modulators of SPP1 in macrophages.
- To develop novel nanoformulations for targeted delivery of SPP1 modulators to TAMs.
- To evaluate the therapeutic potential of identified compounds in preclinical cancer models.
Main Methods:
- Phenotypic screening of small molecules for SPP1 modulation in macrophages.
- Development of a TAM-avid systemic nanoformulation.
- In vitro and in vivo evaluation of lead compound efficacy, including SPP1 downregulation and tumor remission in murine models.
Main Results:
- Identification of several small molecule SPP1 modulators.
- Successful incorporation of hits into a TAM-avid nanoformulation.
- The lead compound, CANDI460, effectively downregulated SPP1 in vitro and in vivo, leading to tumor remissions in various murine models.
Conclusions:
- Small molecule modulation of SPP1 in TAMs represents a promising therapeutic strategy.
- CANDI460-loaded nanoformulations show potential for targeted cancer therapy by reprogramming TAMs.
- These findings open new avenues for developing effective TAM-specific therapeutics.
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