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Paper Abstract

Are molecularly targeted agents completely ruining your paraganglioma?

Myasthenia gravis (MG) is an autoimmune disease affecting neuromuscular junctions of the body. The disease typically presents with autoantibodies in the body (immune proteins produced by the body’s immune system) targeting the nerve-muscle junction to create an immunological attack.

This leads to degradation of neurological signaling for voluntary muscle movement leading to muscle weakness in MG patients. The muscles frequently affected are those of the eyes, extremities, and throat in the body. Muscle weakness in the respiratory pathways may result in severe respiratory failure which is also called a myasthenic crisis. The initial symptoms of MG include ocular or eye-related symptoms such as drooping of upper eyelids or ptosis, caused by muscle weakness, and/or double vision, which is seen in 80% of the cases.

Is there a need for a new treatment approach for paragangliomas?

Medical disorders like paraganglioma are uncommon. As a result, there are still a few studies, clinical trials, and evidence-based data available in this area. This makes clinical judgments more challenging. The value of treatment for paraganglioma tumors is currently modest. As a result, numerous clinical trials are being done to find a more focused strategy. Several clinical trials are currently registered on Therefore, future treatment alternatives for paragangliomas, including molecularly targeted agents and immunotherapy, may be pertinent [2], [3].

What are molecularly targeted agents?

Molecularly targeted agents (MTAs) are a type of cancer treatment that targets specific molecules that are involved in the growth and progression of cancer. MTAs are a newer type of cancer treatment that is showing promise in the treatment of various types of cancer, including paragangliomas. MTAs are typically used in combination with other cancer treatments, such as surgery and radiation therapy.

What molecularly targeted agents are available for treatment?

There are several MTAs that are currently being studied in the treatment of paraganglioma, including sunitinib, everolimus, axitinib cabozantinib, temsirolimus, and hypoxia-inducible factor inhibitors (HIFs). Clinical trials are now examining the effectiveness of tyrosine kinase inhibitors such as lenvatinib (NCT03008369), cabozantinib (NCT02302833), nivolumab, and ipilimumab (NCT02834013). The justification for the use of pembrolizumab in patients with advanced paragangliomas was recently presented by data from a phase 2 clinical trial [2], [3].


How do molecularly targeted agents work?

One of the promising drugs is sunitinib, which is being studied. Following a comprehensive consultation, sunitinib has been selected as a second-line treatment option. Sunitinib is administered orally and is a multitargeted inhibitor of receptor tyrosine kinases. It targets the platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), KIT, and FLT3 to have antiangiogenic and anticancer actions.


Additionally, everolimus is a mTOR pathway inhibitor, making it a possible target for future treatments. The combination therapy was suggested to maximize its efficacy, and further cell line tests revealed that everolimus in combination therapies is more successful than alone. Furthermore, the numerous tyrosine kinase inhibitors axitinib and cabozantinib are being evaluated in combination therapy for metastatic, recurring, or primary unresectable paragangliomas.


Another promising but still inadequately studied drug in paraganglioma is hypoxia-inducible factor inhibitors (HIFs). HIF-2a inhibitors may be helpful and effective in treating patients with clear-cell renal cell carcinoma, according to recent studies. HIFs appear to be appropriate targets in paraganglioma since both tumors have similar molecular drivers. According to the currently available information, HIF-2a is overexpressed in paraganglioma although HIF1-a is not. Therefore, two HIF-2a-targeting clinical trials are currently with active and have recruiting status on The first is a phase II study of Belzutifan/MK-6482 monotherapy in advanced pheochromocytoma or paraganglioma (NCT04924075), and the other is a phase I study of DFF332 in combination with everolimus, spartalizumab, plus taminadenant in clear-cell renal-cell carcinoma and advanced hereditary paraganglioma (NCT04895748) [1]–[3].

What are the benefits of molecularly targeted agents for paraganglioma patients?

The quality of life is comprised in paraganglioma patients despite the presence of varied therapeutic options, as existing therapies have long-term side effects. Thus, a newer therapeutic option like targeted therapy has many advantages, such as:

  • Less toxicity and side effects

  • It offers longer survival time and

  • It improves the quality of life


Current research offers new ideas for targeted therapies for paragangliomas by focusing on the signal pathways. In a nutshell, significant progress has been made [3].

To wrap things up

The use of MTAs in the treatment of paragangliomas is a relatively new concept, and additional research is required to ascertain the efficacy of these drugs in this disease. These agents are more specific to the genetic alterations that cause paraganglioma and are less likely to cause side effects. MTAs are therefore hold promise as a potential treatment option for patients with paragangliomas. However, because of the complexity of tumor pathogenesis, further studies on the biology of paraganglioma tumors is mandatory to identify new target genes and targeted drugs to enhance the prognosis and survival of patients with paraganglioma.


  1. F. Sesti et al., “Sunitinib Treatment for Advanced Paraganglioma: Case Report of a Novel SDHD Gene Mutation Variant and Systematic Review of the Literature,” Frontiers in Oncology, vol. 11, 2021, Accessed: Oct. 27, 2022. [Online]. Available:

  2. B. Winzeler, B. G. Challis, and R. T. Casey, “Precision Medicine in Phaeochromocytoma and Paraganglioma,” J Pers Med, vol. 11, no. 11, p. 1239, Nov. 2021, DOI: 10.3390/jpm11111239.

  3. B. K. Sobocki, A. Perdyan, O. Szot, and J. Rutkowski, “Management of Pheochromocytomas and Paragangliomas: A Case-Based Review of Clinical Aspects and Perspectives,” J Clin Med, vol. 11, no. 9, p. 2591, May 2022, DOI: 10.3390/jcm11092591.


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