Gastrointestinal Stromal Tumor (GISTs) represent a compelling and challenging area within oncology, demanding sophisticated preclinical development strategies. At Protheragen, we offer comprehensive diagnostics and therapeutics development services for GISTs.
Overview of Gastrointestinal Stromal Tumor (GIST)
Gastrointestinal Stromal Tumor (GISTs) represent a distinct subset of mesenchymal tumors arising from the gastrointestinal (GI) tract, primarily originating from the interstitial cells of Cajal (ICCs). These tumors are characterized by specific molecular alterations, most notably mutations in the KIT or PDGFRA genes, which drive their pathogenesis. GISTs can occur throughout the GI tract, with the stomach and small intestine being the most common sites. The annual incidence ranges from 6 to 22 cases per million individuals globally, making GISTs the most common form of sarcoma in the GI tract.
Fig.1 Driver mutations of molecular Gastrointestinal Stromal Tumor (GIST) subtypes. (Blay J. Y.,
et al., 2021)
Pathogenesis of Gastrointestinal Stromal Tumor (GIST)
The pathogenesis of GISTs is predominantly driven by activating mutations in receptor tyrosine kinases (RTKs), particularly KIT and PDGFRA. These mutations lead to constitutive activation of the respective kinases, resulting in uncontrolled cell proliferation and survival. Approximately 80% of GISTs harbor KIT mutations, while 5-7% have PDGFRA mutations. Other molecular drivers include rare gene fusions involving RTKs, mutations in downstream signaling pathways, and loss-of-function alterations in succinate dehydrogenase (SDH) subunits. These genetic alterations result in the activation of downstream signaling pathways such as PI3K-AKT, JAK-STAT, and RAS-RAF-MEK-ERK (MAPK), which contribute to tumor growth and progression.
Diagnostics Development for Gastrointestinal Stromal Tumor (GIST)
Immunohistochemical (IHC) Markers
Immunohistochemical (IHC) markers play a crucial role in the diagnosis of GISTs. CD117 (KIT) and DOG1 are the most commonly used IHC markers, with CD117 being expressed in approximately 95% of GISTs and DOG1 in over 90%. These markers are highly sensitive and specific, aiding in the differentiation of GISTs from other mesenchymal tumors. For instance, CD117-negative GISTs often express DOG1, making it a valuable marker for diagnosing such cases.
Molecular Analysis
Molecular analysis is essential for identifying specific mutations in KIT and PDGFRA genes. This information guides therapeutic strategies, as different mutations may respond differently to targeted therapies. For example, GISTs with KIT exon 11 mutations are highly sensitive to imatinib, while those with PDGFRA D842V mutations are resistant to this drug but can be treated with avapritinib. Comprehensive molecular profiling also helps identify other genetic alterations, such as BRAF V600E mutations or NF1 loss, which are less common but still significant in guiding therapy.
Therapeutics Development for Gastrointestinal Stromal Tumor (GIST)
- Tyrosine Kinase Inhibitors (TKIs)
TKIs have revolutionized the therapeutic of GISTs. Imatinib was the first TKI approved for advanced GISTs and remains a cornerstone of therapy. Other TKIs, such as sunitinib, regorafenib, and ripretinib, have been developed to address resistance to imatinib. Avapritinib is a type I TKI effective against PDGFRA mutations, including the D842V mutation. These drugs target the constitutively active kinases, leading to tumor regression and improved patient outcomes.
- Antibody-Drug Conjugates (ADCs)
ADCs, such as DS-6157a, target specific antigens on GIST cells, delivering cytotoxic agents directly to the tumor cells. This targeted approach aims to reduce systemic toxicity while maximizing therapeutic efficacy. DS-6157a, which targets GPR20, has shown antitumor activity in preclinical models and is currently being evaluated in human trials.
Table 1. Predicted efficacy of novel therapeutic strategies against common subtypes of GIST. (Klug L. R., et al., 2022)
| Therapeutic strategy |
Novel therapeutic |
Target |
Predicted efficacy |
| KIT-mutant GIST |
PDGFRA-mutant GIST |
SDH-deficient GIST |
| TKI-based |
THE-630 (NCT05160168) |
KIT driver (all known primary and secondary variants) |
√ |
x |
x |
| NB003 (NCT04936178), formally known as AZD3229 |
KIT or PDGFRA driver |
√ |
√ |
x |
| Bezuclastinib (previously known as CGT9486 and PLX9486) + sunitinib (NCT05208047) |
KIT driver |
√ |
√ |
x |
| TKI + MEKi (such as imatinib plus binimetinib; NCT01991379) |
KIT or PDGFRA driver |
√ |
√ |
x |
| TKI + PI3Ki + MEKi (140) |
KIT or PDGFRA driver |
√ |
√ |
x |
| ADC |
DS-6157a (NCT04276415) |
GPR20 |
√ |
√ |
√ |
| RLT |
177Lu-NeoB (NCT03872778) |
GRPR (expression determined by 68Ga-NeoB uptake) |
√ |
unknown |
unknown |
| DDR |
Temozolomide (NCT03556384) |
SDH-deficient cells (negative for MGMT expression) |
x |
x |
√ |
| IO |
TKI + ICI (such as axitinib and avelumab; NCT04258956) |
KIT or PDGFRA driver and PD-1 or PD-L1 |
√ |
√ |
x |
| TKI + immunostimulant (such as IFNα167) |
KIT or PDGFRA driver and cytokine receptors |
√ |
√ |
x |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen is a leading provider of comprehensive diagnostic and therapeutic development services for Gastrointestinal Stromal Tumors (GISTs). By harnessing state-of-the-art technologies and our profound expertise in molecular biology, pathology, and pharmacology, we offer a suite of advanced services. These encompass sophisticated molecular profiling, precise IHC marker analysis, and rigorous preclinical testing of innovative therapies.
Disease Models
- Primary Cell Cultures
- Immortalized Cell Lines
- Trp53 Mutation Models
- Kit-Asp818Tyr Mutation Models
- Chemically Induced GIST Models
Protheragen is committed to delivering customized solutions that are meticulously tailored to address the unique requirements of each client, thereby ensuring that every project is meticulously designed to attain the most optimal outcomes. If you are interested in our services, please feel free to contact us.
References
- Blay, Jean-Yves, et al. "Gastrointestinal stromal tumours." Nature reviews Disease primers 7.1 (2021): 22.
- Klug, Lillian R., et al. "New treatment strategies for advanced-stage gastrointestinal stromal tumours." Nature reviews Clinical oncology 19.5 (2022): 328-341.
- Wu, Chiao-En, et al. "Clinical diagnosis of gastrointestinal stromal tumor (GIST): from the molecular genetic point of view." Cancers 11.5 (2019): 679.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
