Theratechnologies Announces Publication in Frontiers in Immunology that Deepens Understanding of Sudocetaxel Zendusortide (TH1902) Molecular Mechanism of Action
Theratechnologies Inc. announces preclinical research results demonstrating the potential of sudocetaxel zendusortide in activating immune defense mechanisms and enhancing anti-PD-L1 immune-mediated tumor cell killing in triple-negative breast cancer. The publication highlights the superior tumor growth inhibition and immune cell infiltration compared to docetaxel in a murine tumor model, suggesting new avenues for combining immunotherapy with sudocetaxel zendusortide.
The preclinical findings for sudocetaxel zendusortide, a peptide-drug conjugate targeting the sortilin receptor, are significant in the field of oncology drug development. The ability to trigger the cGAS/STING pathway, which is crucial for innate immunity, represents a promising mechanism for enhancing the efficacy of cancer treatments. This pathway acts as a cellular alarm system that detects and responds to DNA damage in cells, which can be a result of cancerous transformations.
The research suggests that sudocetaxel zendusortide not only directly inhibits tumor growth but also modulates the tumor microenvironment to become more receptive to immune system attacks. This is particularly noteworthy in 'cold' tumors, which typically exhibit less immune cell infiltration and are often resistant to immunotherapies. The reported increase in leukocyte infiltration, including tumor-infiltrating lymphocytes and tumor-associated macrophages, indicates potential for turning 'cold' tumors into 'hot' tumors, which are more responsive to immunotherapy.
Furthermore, the combination with anti-PD-L1 checkpoint inhibitors could represent a synergistic approach, potentially overcoming resistance to single-agent immunotherapies. This could lead to broader applicability of immunotherapies across various cancer types, including difficult-to-treat triple-negative breast cancer (TNBC).
From a clinical perspective, the results of sudocetaxel zendusortide in a TNBC-derived xenograft model are particularly encouraging. TNBC is a subtype of breast cancer that lacks the expression of estrogen receptor, progesterone receptor and HER2, making it challenging to treat with targeted therapies. The reported complete and prolonged tumor regression in this model suggests a potential new avenue for treatment where options are currently limited.
The enhancement of anti-tumor immunity by activating the cGAS/STING pathway could be a game-changer in oncology. This pathway is involved in sensing cytoplasmic DNA, leading to the production of type I interferons and other cytokines that promote anti-tumor immunity. By potentiating anti-PD-L1 immune-mediated tumor cell killing, sudocetaxel zendusortide may improve the outcomes for patients who are not currently benefiting from existing immunotherapies.
It is also important to consider the safety profile and potential side effects when evaluating the transition from preclinical models to human trials. The balance between efficacy and tolerability is critical for the success of new cancer treatments.
The advancement of sudocetaxel zendusortide through preclinical stages could have a notable impact on the biopharmaceutical market, particularly within the oncology segment. As a first-in-class peptide-drug conjugate, its potential to improve immunotherapy outcomes could position it favorably in a market that is increasingly focused on combination therapies and personalized medicine.
The growing prevalence of cancer and the push for more effective treatments drive the demand for innovative therapies like sudocetaxel zendusortide. If subsequent clinical trials confirm the preclinical results, the drug could capture a significant share of the market, especially for cancers with limited treatment options like TNBC.
Investors and stakeholders in the biopharmaceutical industry should monitor the progress of this drug closely as it moves towards clinical trials. The success of sudocetaxel zendusortide could also attract partnership opportunities, licensing deals, or even acquisition interest from larger pharmaceutical companies looking to expand their oncology portfolios.
02/20/2024 - 07:30 AM
Publication pinpoints triggering of cGAS/STING pathway to activate immune defense mechanisms, as well as potentiation of anti-PD-L1 immune-mediated tumor cell killing, in triple-negative breast cancer xenograft model Weekly administration of single agent sudocetaxel zendusortide demonstrated superior tumor growth inhibition and immune cell infiltration compared to docetaxel in “cold” murine tumor model Preclinical results suggest new approaches for broadening immunotherapy utilization in combination with sudocetaxel zendusortide MONTREAL, Feb. 20, 2024 (GLOBE NEWSWIRE) -- Theratechnologies Inc. (“Theratechnologies” or the “Company”) (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, today announced the publication of a peer-reviewed article in Frontiers in Immunology that enhances understanding of the molecular mechanism of action of sudocetaxel zendusortide (also known as TH1902) as a potential anticancer treatment. Sudocetaxel zendusortide is an investigational, first-in-class peptide-drug conjugate (PDC) that targets the sortilin receptor (SORT1) and expedites the internalization and delivery of the cytotoxic payload (docetaxel) directly into cancer cells.
The article, “Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing ” appears in the “Cancer Immunity and Immunotherapy” section of the February (Volume 15) issue of the journal. It reports on preclinical research in which sudocetaxel zendusortide induced complete and prolonged tumor regression in a triple-negative breast cancer (TNBC)-derived xenograft tumor model and demonstrated tumor regression associated with growth inhibition and immune cell infiltration in a “cold” murine (syngeneic) tumor model. Additionally, combining sudocetaxel zendusortide with an anti-PD-L1 checkpoint inhibitor led to increases in tumor growth inhibition and median animal survival.
“The results published in Frontiers in Immunology demonstrate that sudocetaxel zendusortide exerts its antitumor activity, in part, through modulation of the immune tumor microenvironment,” said Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer at Theratechnologies, and one of the paper’s co-authors. “Our findings reinforce that combining this novel peptide-drug conjugate with anti-PD-L1 checkpoint inhibitor therapy may yield improved clinical outcomes, with potentially profound implications for patients across various cancer types.”
“An important aspect of our research is the activation of an antitumor immunity process through involvement of the cGAS/STING pathway, a key regulator in the cancer-immunity cycle,” commented Prof. Borhane Annabi, Chair in Cancer Prevention and Treatment in the Chemistry Department at the Université du Québec à Montréal, and a co-author of the Frontiers in Immunology paper. “Although the animal tumor model we worked with is considered a non-immunogenetic, or ‘cold’ tumor model, we observed a net increase in leukocyte infiltration within sudocetaxel zendusortide-treated tumors, especially for tumor-infiltrating lymphocytes and tumor-associated macrophages. This realization supports the rationale for further exploration of the combination of sudocetaxel zendusortide with immunotherapy.”
The article can be accessed online here .
About Immunotherapy in Cold and Hot Tumors
Immunotherapies have significantly improved the treatment of cancer. Researchers continue to explore the power of the immune system to find and destroy cancer cells. “Hot” tumors show signs of inflammation, meaning the tumor has already been infiltrated by immune cells rushing to fight the cancerous cells. Only a few types of cancers are considered to be hot. “Cold” tumors have not yet been infiltrated with T cells. This signals that the immune response is not working, making it difficult to provoke an immune response with immunotherapies. Most cancers of breast, ovary, prostate, pancreas, and brain (e.g., glioblastoma [GBM]) are cold tumors, and are largely treated with traditional therapies like radiation and chemotherapy. As a result, researchers have sought to understand how to turn cold tumors hot by reversing the suppressive microenvironment surrounding cold tumors and by attracting more of the “right” anti-tumor lymphocytes.
About Sudocetaxel Zendusortide (TH1902) and SORT1+ Technology™
Sudocetaxel zendusortide is a first-of-its-kind sortilin receptor (SORT1)-targeting PDC, and the first compound to emerge from the Company’s broader licensed oncology platform. As a new chemical entity, sudocetaxel zendusortide employs a cleavable linker to conjugate (attach) a proprietary peptide to docetaxel, a well-established cytotoxic chemotherapeutic agent used to treat many cancers. The FDA granted Fast Track designation to sudocetaxel zendusortide as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial in individuals with advanced ovarian cancer.
Theratechnologies has established the SORT1+ TechnologyTM platform as an engine for the development of PDCs that target SORT1, which is expressed in multiple tumor types. SORT1 is a “scavenger” receptor that plays a significant role in protein internalization, sorting, and trafficking. Expression of SORT1 is associated with aggressive disease, poor prognosis, and decreased survival. It is estimated that SORT1 is expressed in 40% to 90% of endometrial, ovarian, colorectal, triple-negative breast (TNBC), and pancreatic cancers, making this receptor an attractive target for anticancer drug development.
About Theratechnologies
Theratechnologies (TSX: TH) (NASDAQ: THTX) is a biopharmaceutical company focused on the development and commercialization of innovative therapies addressing unmet medical needs. Further information about Theratechnologies is available on the Company's website at www.theratech.com , on SEDAR+ at www.sedarplus.ca and on EDGAR at www.sec.gov . Follow Theratechnologies on Linkedin and X (formerly Twitter).
Forward-Looking Information
This press release contains forward-looking statements and forward-looking information (collectively, the “Forward-Looking Statements”) within the meaning of applicable securities laws, that are based on management’s beliefs and assumptions and on information currently available to it. You can identify forward-looking statements by terms such as “may”, “will”, “should”, “could”, “promising”, “would”, “outlook”, “believe”, “plan”, “envisage”, “anticipate”, “expect” and “estimate”, or the negatives of these terms, or variations of them. The Forward-Looking Statements contained in this press release include, but are not limited to, statements regarding the combination of sudocetaxel zendusortide with anti-PD-L1 checkpoint inhibitor therapy which may yield improved clinical outcomes, the potential treatment of various types of cancer with sudocetaxel zendusortide, the development of PDCs resulting from the SORT1+ TechnologyTM platform and our estimates regarding the expression of SORT1 in various types of cancer. Although the Forward-Looking Statements contained in this press release are based upon what the Company believes are reasonable assumptions in light of the information currently available, investors are cautioned against placing undue reliance on these statements since actual results may vary from the Forward-Looking Statements contained in this press release. These assumptions include, without limitation, that the results observed in pre-clinical testing will be replicated into humans, sudocetaxel zendusortide will be able to treat various types of cancer, the Company will be successful in developping addtional PDCs from the SORT1+ TechnologyTM platform and positive safety and efficacy results will be observed from the current Phase 1 clinical trial studying sudocetaxel zendusortide. Forward-Looking Statements assumptions are subject to a number of risks and uncertainties, many of which are beyond the Company’s control, that could cause actual results to differ materially from those that are disclosed in or implied by such Forward-Looking Statements. These risks and uncertainties include, but are not limited to, the inability of sudocetaxel zendusortide to demonstrate efficacy results when used in human subjects, limitations in the types of cancer for which sudocetaxel zendusortide could be used and limitations in the capacity of the Company to develop new PDCs. We refer current and potential investors to the “Risk Factors” section of our Annual Information Form dated February 27, 2023, available on SEDAR+ at www.sedarplus.ca and on EDGAR at www.sec.gov as an exhibit to our report on Form 40-F dated February 28, 2023, under Theratechnologies’ public filings. The reader is cautioned to consider these and other risks and uncertainties carefully and not to put undue reliance on forward-looking statements. Forward-Looking Statements reflect current expectations regarding future events and speak only as of the date of this press release and represent our expectations as of that date.
We undertake no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise, except as may be required by applicable law.
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What is the potential anticancer treatment discussed in the article?
The potential anticancer treatment discussed in the article is sudocetaxel zendusortide (TH1902).
What is the molecular mechanism of action of sudocetaxel zendusortide?
Sudocetaxel zendusortide targets the sortilin receptor (SORT1) and expedites the internalization and delivery of the cytotoxic payload (docetaxel) directly into cancer cells.
What were the key findings of the preclinical research?
The preclinical research showed complete and prolonged tumor regression in a triple-negative breast cancer-derived xenograft tumor model and tumor regression associated with growth inhibition and immune cell infiltration in a 'cold' murine tumor model.
How did combining sudocetaxel zendusortide with an anti-PD-L1 checkpoint inhibitor impact tumor growth?
Combining sudocetaxel zendusortide with an anti-PD-L1 checkpoint inhibitor led to increases in tumor growth inhibition and median animal survival.
What is the significance of the activation of the cGAS/STING pathway in the research?
The activation of the cGAS/STING pathway is crucial in triggering an antitumor immunity process and modulating the immune tumor microenvironment.
