Introduction to Desmoid tumors, and Gamma-Secretase Inhibitor Nirogacestat

Desmoid tumors, also known as aggressive fibromatosis, are uncommon non-metastatic soft tissue tumors distinguished by the proliferation of fibroblasts and myofibroblasts [Kasper, 2024]. The majority of instances occur in the abdomen wall, mesentery, and chest wall; nevertheless, desmoid fibromatosis has also been reported in the craniofacial area [Baabdullah, 2021].  

These cancers frequently infiltrate neighboring tissues, posing major morbidity and therapy problems [Federman, 2022]. Though they do not spread to other organs, their local aggressiveness can cause serious issues, particularly when they target essential systems like blood arteries, nerves, or organs.  

Nirogacestat, a ??-secretase inhibitor (GSI), represents a substantial progress in the treatment of desmoid malignancies [SpringWorks, 2023]. This oral medicine provides a focused strategy to treating these difficult malignancies. This article discusses desmoid tumors and the therapeutic potential of Nirogacestat.  

Desmoid Tumors: Characteristics and Pathogenesis

Desmoid tumors develop from connective tissue and can occur anywhere in the body [DTRF, 2024]. They are often classified as benign tumors due to their low spreading potential; yet, their aggressive local development frequently necessitates surgical intervention or systemic medication.  

Desmoid tumors may be caused by mutations in the CTNNB1 gene (encoding β-catenin) or the APC gene (encoding adenomatous polyposis coli) in FAP patients. These genetic alterations impair the Wnt/β-catenin signaling pathway, resulting in uncontrolled cell proliferation [Lazar, 2008]. These findings are exacerbated by the fact that desmoid tumors are heterogeneous [De Bellis, 2024]. Hormonal factors, notably estrogen, are thought to have a role since the tumors are more prevalent in women and frequently arise during the reproductive years [Lim, 1986].  

Clinical Presentation and Challenges

Desmoid tumors generate a wide range of symptoms, depending on their location and size. Patients may experience soreness, swelling, or decreased function in the affected locations. Tumors located near vital tissues can cause life-threatening complications such as intestinal obstruction, vascular compression, or nerve entrapment.   

Desmoid tumors are difficult to control because of their erratic development pattern. While some remain constant or regress naturally, others show fast advancement [Agulnik, 2024]. Because of this heterogeneity, treatment strategies must be tailored to the patient's symptoms, tumor behavior, and general health.  

Current Treatment Options

Historically, surgery was the main therapy for desmoid tumors. However, significant recurrence rates (up to 50%) after surgical excision have moved the emphasis to less invasive treatments. [Agulnik, 2024]. Current therapeutic options include:  

1. Watchful waiting: is suggested for asymptomatic or stable tumors, as some may regress without treatment.  

2. Surgical Resection: Saved for tumors that are producing serious problems or symptoms.  

3. Radiation therapy: is used as an adjuvant to lessen recurrence or in situations when surgery is not practical.  

4. Systemic therapies: Tyrosine kinase inhibitors, hormone therapy (such as tamoxifen), chemotherapy, and non-steroidal anti-inflammatory medications (NSAIDs) are examples.

Notwithstanding these choices, a number of medications have substantial adverse effects or low efficacy, underscoring the need for innovative treatments.  

Nirogacestat: A Targeted Approach

A selective ??-secretase inhibitor, nirogacestat targets the Notch signaling system, which is linked to the pathophysiology of desmoid tumors [Campos, 2024]. The ??-secretase is essential for Notch receptor activation, and its suppression impairs the survival and proliferation of tumor cells.  

The phase III DeFi study, which showed notable increases in progression-free survival (PFS) and symptom reduction in patients with desmoid tumors, proved the effectiveness of nirogacestat. [SpringWorks, 2023] Nirogacestat was proven to be a potential therapy option by this crucial trial, particularly for individuals with recurring or incurable malignancies.  

Mechanism of Action

Nirogacestat and other selective ??-secretase inhibitors stop Notch receptors from being cleaved, which stops their downstream signaling. The expression of genes involved in angiogenesis and tumor development is decreased by this disruption. Furthermore, Nirogacestat further inhibits the growth of desmoid tumors by indirectly influencing Wnt/β-catenin signaling [SpringWorks, 2023].  

Clinical Evidence Supporting Nirogacestat 

For the DeFi trial, 142 individuals with progressing desmoid tumors were recruited, a double-blind, randomized investigation [ESMO, 2022]. Nirogacestat or a placebo was administered to the participants. Among the main conclusions were:

· PFS: PFS: When compared to a placebo, nirogacestat decreased the risk of disease progression by 71%.

· Symptom Relief: Notable decreases in pain and suffering associated with the tumor were documented.  

· Safety Profile: The majority of adverse events were mild to severe, with diarrhea, tiredness, and nausea being the most prevalent [SpringWorks, 2023a].

These findings highlight Nirogacestat's potential as a well-tolerated and effective treatment for desmoid tumor.  

Advantages of Nirogacestat 

Nirogacestat has various benefits over other therapies.  

1. Non-Invasive: Because it is taken orally, it does not require surgery or hospitalization.  

2. Targeted Action: Its mechanism directly targets pathways involved in tumor development, increasing effectiveness.

3. Improved Quality of Life: Nirogacestat allows patients to resume normal activities by relieving symptoms and stopping tumor development.

4. Reasonable price: A supply of 180 pills (50 mg) costs around US$ 30,547 for cash-paying consumers. However, patient assistance programs and copay vouchers are available to help qualified patients minimize their costs [Drugs.com, 2024].

Future Directions and Challenges

While Nirogacestat represents a major breakthrough, challenges remain:

1. Further research: is needed to determine the long-term effects of sustained ??-secretase inhibition on normal tissues.   

2. Resistance Mechanisms: Potential resistance to gamma-secretase inhibitors requires long-term studies to fully understand the risk.

Future research will look at the usage of Nirogacestat in conjunction with BCMA-targeting medicines to treat relapsed or refractory multiple myeloma [Melamed, 2020].  

Conclusion

Desmoid tumors, though benign, pose significant challenges due to their aggressive local growth and impact on quality of life. Traditional treatments such as surgery and systemic therapies often yield suboptimal outcomes.

Nirogacestat, a ??-secretase inhibitor, offers a promising new option for managing desmoid tumors. Its targeted mechanism of action and favorable clinical outcomes make it a valuable addition to the therapeutic arsenal.

As research continues to uncover the full potential of Nirogacestat, it is poised to transform the treatment landscape for desmoid tumors, offering hope to patients who have long faced limited options.

REFERENCES

Agulnik, M. (2024, December 23). Understanding when to choose systemic treatment for desmoid tumors. Targeted Oncology. https://www.targetedonc.com/view/understanding-when-to-choose-systemic-treatment-for-desmoid-tumors

Baabdullah, R., Gigliotti, J., Makhoul, N., & Jung, S. (2021, June 7). Desmoid fibromatosis of the maxillofacial region: A case report and review of the literature. Oral Health, https://www.oralhealthgroup.com/features/desmoid-fibromatosis-of-the-maxillofacial-region-a-case-report-and-review-of-the-literature/

Campos, F., & Kasper, B. (2024). Examining nirogacestat for adults with progressing desmoid tumors who require systemic treatment. Expert Opinion on Pharmacotherapy, 25(16), 2115–2124. https://doi.org/10.1080/14656566.2024.2418416

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DTRF. (2024, March 1). What is a desmoid tumor?. The Desmoid Tumor Research Foundation. https://dtrf.org/about-desmoid-tumors/what-is-a-desmoid-tumor/

ESMO. (2022, September 10). DEFI trial: Smart Design and impressive results for the benefit of patients with rare cancers [ESMO congress 2022 press release]. ESMO. https://www.esmo.org/newsroom/press-and-media-hub/esmo-media-releases/defi-trial-smart-design-and-impressive-results-for-the-benefit-of-patients-with-rare-cancers

Federman, N. (2022). Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition. npj Precision Oncology, 6(1), 62. https://doi.org/10.1038/s41698-022-00308-1

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Melamed, D. (2020, November 9). New nirogacestat combos to enter myeloma trials, SpringWorks says. Rare Cancer News. https://rarecancernews.com/news/springworks-announces-two-collaborations-trials-nirogacestat-combos-for-myeloma/

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SpringWorks. (2023, November 27). Springworks Therapeutics announces FDA approval of OGSIVEOTM (nirogacestat) as the first and only treatment for adults with desmoid tumors. GlobeNewswire News Room. https://www.globenewswire.com/news-release/2023/11/27/2786554/0/en/SpringWorks-Therapeutics-Announces-FDA-Approval-of-OGSIVEO-nirogacestat-as-the-First-and-Only-Treatment-for-Adults-with-Desmoid-Tumors.html

About the Author:

David Orchard-Webb,

Ph.D., is a technical writer with broad interests including health & technology writing, plus extensive training and knowledge of biomedicine and microbiology. My Ph.D. and postdoc were in oncology and developing cancer medicines. I provide technical medical and other writing services for projects ranging from “knowledge automation” to pure pharma, to food safety, to the history of science, and everything in between. I also provide white papers, ebooks, meta-analysis reviews, editing, consulting, business, and market research-related activities in biomedicine, technology, and health. In addition to its well-known role in the development of medicines, I am a big believer in biotechnology’s ability to revolutionize industries such as food-tech, agtech, textiles & fashion.