Tumor suppressor SALL1 as a therapeutic agent for treating cancer
Inventors
Peng, Guangyong • RAUCHMAN, Michael • MA, Chunling • Wang, Fang
Assignees
St Louis University • US Department of Veterans Affairs
Publication Number
US-10618944-B2
Publication Date
2020-04-14
Expiration Date
2036-02-26
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Abstract
The present disclosure relates to the SALL1 tumor suppressor. Methods of employing SALL1 to treat cancer, as well as the underlying mechanism by which this occurs, also are described.
Core Innovation
The invention relates to the use of the SALL1 tumor suppressor as a therapeutic agent for treating cancer, particularly breast cancer and prostate cancer. It involves methods employing isolated polynucleotides encoding SALL1 operably connected to heterologous promoters that are active in mammalian cancer cells, as well as expression vectors containing these polynucleotides for gene therapy. The invention further encompasses methods suppressing tumor growth, proliferation, migration, or metastasis by contacting cancer cells with SALL1 expression cassettes or SALL1 polypeptides, including combinations with other anti-cancer therapies.
The problem being solved addresses the lack of understanding of the role of SALL1 in human cancers and the need for improved cancer therapies. While other SALL family members have been implicated in tumorigenesis, the molecular mechanism and causative role of SALL1 in cancer, especially breast cancer, are poorly understood. Prior evidence showed SALL1 is downregulated in breast cancer and acts as a tumor suppressor, but the mechanism of its action and how it can be utilized therapeutically remained unclear.
The invention solves this by demonstrating that SALL1 suppresses breast cancer cell growth and proliferation by inducing cell cycle arrest and cellular senescence. This tumor suppressive activity depends on SALL1's ability to recruit the nucleosome remodeling and deacetylase (NuRD) corepressor complex. Signaling pathways including MAPK p38, ERK1/2, and mTOR control this mechanism. The disclosure details compositions and methods for delivering SALL1 polynucleotides or polypeptides into cancer cells using various promoters and viral or non-viral expression vectors, thereby inhibiting tumorigenesis and metastasis in cancer models in vitro and in vivo.
Claims Coverage
There is one independent claim that discloses a therapeutic method for cancer treatment, specifically focusing on suppressing growth and metastasis of breast and prostate cancer cells.
Use of SALL1 expression cassette to suppress cancer cell growth and metastasis
A method comprising contacting breast or prostate cancer cells with an expression cassette containing a polynucleotide encoding SALL1 under control of a promoter operable in eukaryotic cells, resulting in suppression of growth, proliferation, migration, and metastasis of the cancer cells.
Use of heterologous promoters to drive SALL1 expression
Employing a heterologous promoter operable in cancer cells, selected from specific promoters including hsp68, SV40, CMV, MKC, GAL4UAS, HSV, and β-actin, to control SALL1 expression in the expression cassette.
Use of tissue-specific or inducible promoters for SALL1 expression
Incorporation of either tissue-specific or inducible promoters to control SALL1 expression in cancer cells.
Delivery of SALL1 expression cassette via replication-competent vectors
Use of replication-competent expression vectors containing the SALL1 expression cassette, including viral vectors such as retroviral, adenoviral, adeno-associated, vaccinia, and herpesviral vectors.
Delivery of SALL1 expression cassette via non-viral vectors
Use of non-viral replication-competent expression vectors encapsulated in lipid delivery vehicles or nanoparticles to deliver SALL1 expression cassettes.
Inclusion of polyadenylation signals in expression cassette
Expression cassettes may further comprise polyadenylation signals to enhance expression or stability.
Combination therapy with SALL1 and second anti-cancer therapies
Methods further comprising contacting cancer cells with additional anti-cancer therapies including radiation therapy, gene therapy, hormonal therapy, immunotherapy, toxin therapy, or surgery.
Modes of administration for SALL1 expression cassette
Systemic, local or regional administration of the expression cassette, including intra-tumoral injection or administration to a resected tumor bed, with possible repeated administration cycles.
Assessment of SALL1 in patient samples
Methods may additionally include assessing SALL1 structure, expression, or function in samples from subjects receiving therapy.
The independent claim covers a method for suppressing breast and prostate cancer cell growth and metastasis via expression of SALL1 from heterologous promoters in viral or non-viral vectors, optionally combined with other anti-cancer therapies and diverse administration routes.
Stated Advantages
SALL1 functions as a tumor suppressor in breast cancer by inhibiting tumor cell growth, proliferation, migration, and metastasis.
SALL1-mediated tumor suppression occurs through induction of cellular senescence and cell cycle arrest independent of apoptosis.
The tumor suppressive mechanism depends on SALL1's recruitment of the NuRD complex and regulation via MAPK p38, ERK1/2, and mTOR signaling pathways.
Delivery of SALL1 expression cassettes or polypeptides provides a novel therapeutic strategy for treating breast cancer and potentially other cancers.
Combination of SALL1 therapies with traditional chemo-, radio-, or immunotherapies may improve treatment efficacy.
Documented Applications
Use of SALL1 expression cassettes or polypeptides for treating breast cancer by suppressing tumor growth, proliferation, migration and metastasis.
Use of SALL1 expression cassettes or polypeptides for treating prostate cancer.
Combination cancer therapies involving SALL1 gene or protein delivery with radiation therapy, gene therapy, hormonal therapy, immunotherapy, toxin therapy or surgery.
In vivo administration of SALL1 agents systemically, locally, regionally, intra-tumorally or to resected tumor beds for cancer therapy.
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