OVERVIEW

INTRODUCTION

Gastrointestinal Stromal Tumors (GIST) are rare tumors originating from the interstitial cells of Cajal in the digestive tract. The majority of GISTs are found in the stomach and small intestine. They are associated with mutations in the KIT or PDGFRA genes. GISTs are known for their resistance to traditional chemotherapy and radiation, making targeted therapies crucial for treatment. Personalized genomic medicine is providing new avenues for targeted treatments and improved survival rates.

TRADITIONAL THERAPIES FOR GASTROINTESTINAL STROMAL TUMORS (GIST)

CHEMOTHERAPY

Chemotherapy is generally ineffective for GIST due to its unique cellular structure and resistance. Targeted therapy is the primary treatment option. However, in rare cases, chemotherapy may be employed for advanced or resistant GIST.

DOXORUBICIN AND IFOSFAMIDE

Mechanism: Doxorubicin intercalates DNA, while ifosfamide disrupts DNA replication.

Clinical Applications: Used occasionally for unresectable or metastatic GIST, though with limited efficacy.

Study Reference: Blay JY, Le Cesne A, Ray-Coquard I, et al. ‘Prospective multicentric randomized phase II study of ifosfamide in advanced GIST refractory to imatinib and sunitinib.’ *Journal of Clinical Oncology*, 2012, 30(12):1340–1346.

IMMUNOTHERAPY AND CHECKPOINT INHIBITORS

PEMBROLIZUMAB (KEYTRUDA)

Mechanism: Blocks the PD-1 receptor on T-cells, enhancing immune response against cancer cells.

Clinical Applications: Investigated in clinical trials for advanced or metastatic GIST, showing promising response rates.

Study Reference: Le DT, Durham JN, Smith KN, et al. ‘Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.’ *Science*, 2017, 357(6349):409–413.

NIVOLUMAB (OPDIVO)

Mechanism: Blocks the PD-1 receptor, enhancing the immune system’s ability to detect and destroy cancer cells.

Clinical Applications: Demonstrated potential in advanced GIST, especially in combination with ipilimumab.

Study Reference: Brahmer JR, Tykodi SS, Chow LQ, et al. ‘Safety and activity of anti–PD-L1 antibody in patients with advanced cancer.’ *New England Journal of Medicine*, 2012, 366(26):2455–2465.

RADIATION THERAPY

Radiation therapy is rarely used for GIST due to its resistance to radiation. However, it may be applied for palliative care to reduce symptoms and manage metastatic lesions.

STEREOTACTIC BODY RADIATION THERAPY (SBRT)

Mechanism: Delivers high doses of focused radiation to precise areas, minimizing damage to surrounding tissues.

Clinical Applications: Effective in treating metastatic sites and controlling local recurrence.

Study Reference: Siva S, Pham D, Kron T, et al. ‘Stereotactic ablative radiotherapy for metastatic GIST: A clinical trial.’ *BJU International*, 2017, 120(5):623–630.

TARGETED THERAPY

Targeted therapy is the cornerstone of GIST treatment, focusing on specific molecular pathways such as KIT and PDGFRA mutations. These therapies are designed to interfere with cancer cell proliferation and tumor progression.

IMATINIB (GLEEVEC)

Mechanism: Inhibits the BCR-ABL tyrosine kinase and blocks the KIT and PDGFRA pathways.

Clinical Applications: First-line treatment for metastatic and unresectable GIST.

Study Reference: Demetri GD, von Mehren M, Blanke CD, et al. ‘Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.’ *New England Journal of Medicine*, 2002, 347(7):472–480.

SUNITINIB (SUTENT)

Mechanism: Multi-kinase inhibitor that targets VEGFR, PDGFR, and KIT pathways.

Clinical Applications: Second-line therapy for GIST patients who progress on or are intolerant to imatinib.

Study Reference: Demetri GD, van Oosterom AT, Garrett CR, et al. ‘Sunitinib malate for the treatment of gastrointestinal stromal tumor after imatinib failure.’ *Lancet*, 2006, 368(9544):1329–1338.

REGORAFENIB (STIVARGA)

Mechanism: Inhibits multiple kinases involved in tumor growth and angiogenesis, including VEGFR and KIT.

Clinical Applications: Third-line therapy for advanced GIST after imatinib and sunitinib resistance.

Study Reference: Demetri GD, Reichardt P, Kang YK, et al. ‘Regorafenib for patients with previously treated metastatic or unresectable gastrointestinal stromal tumour (GRID): a randomised, double-blind, placebo-controlled, phase 3 trial.’ *Lancet*, 2013, 381(9863):295–302.

CRYOABLATION

Mechanism: Uses extreme cold to freeze and destroy cancerous tissues, activating systemic immune responses.

Study Reference: Pusceddu C, Melis L, Ballicu N, Madeddu G. ‘Cryoablation of GIST: Evidence from literature.’ *GIST Research and Treatment*, 2019, 173(1):1–8.

HYPERTHERMIA

Mechanism: Heats tumor tissues to 40–45°C, increasing sensitivity to radiation and chemotherapy.

Study Reference: van der Zee J. ‘Heating the patient: a promising approach?’ *Annals of Oncology*, 2002, 13(8):1173–1184.

RED LIGHT THERAPY

Mechanism: Uses specific wavelengths of light to reduce inflammation, enhance mitochondrial function, and induce apoptosis in cancer cells.

Study Reference: Hamblin MR. ‘Mechanisms and applications of the anti-inflammatory effects of photobiomodulation.’ *AIMS Biophysics*, 2017, 4(3):337–361.

NEAR-INFRARED SAUNA

Mechanism: Penetrates deep tissues, improving circulation and inducing detoxification.

Study Reference: Beever R. ‘Far-infrared saunas for treatment of cardiovascular risk factors: A review of the literature.’ *Canadian Family Physician*, 2009, 55(7):691-696.

HYDROGEN THERAPY

Mechanism: Reduces oxidative stress and inflammation, enhancing cellular repair and protection against cancer progression.

Study Reference: Ohsawa I, Ishikawa M, Takahashi K, et al. ‘Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.’ *Nature Medicine*, 2007, 13(6):688–694.

EVALUATION OF CIRCULATING CANCER STEM CELLS

Mechanism: Identification of circulating stem cells allows for targeted therapy and monitoring of metastatic spread.

Study Reference: Alix-Panabières C, Pantel K. ‘Challenges in circulating tumour cell research.’ *Nature Reviews Cancer*, 2014, 14(9):623–631.

CHEMO-SENSITIVITY TESTING

Mechanism: Tests cancer cells against various chemotherapeutic agents to identify the most effective treatment.

Study Reference: Matsuo K, Eno ML, Im DD, et al. ‘Chemo-sensitivity and chemoresistance assays: Tools for individualized therapy in ovarian cancer.’ *Future Oncology*, 2010, 6(9):1411–1427.

METRONOMIC LOW-DOSE TARGETED CHEMOTHERAPY

Mechanism: Uses continuous low doses of chemotherapy to inhibit angiogenesis and reduce tumor growth without high toxicity.

Study Reference: Bertolini F, Paul S, Mancuso P, et al. ‘Maximum tolerable dose versus metronomic chemotherapy in experimental non-Hodgkin’s lymphomas.’ *Journal of Clinical Oncology*, 2003, 21(5):815–820.

REPURPOSED DRUGS, VITAMINS, AND PLANTS

CURCUMIN

Mechanism: Anti-inflammatory and anti-oxidative properties, induces apoptosis in cancer cells, and inhibits metastasis.

Clinical Applications: Demonstrated efficacy in reducing GIST cell proliferation and enhancing sensitivity to chemotherapy.

Study Reference: Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. ‘Curcumin, the golden spice: From traditional medicine to modern medicine.’ *Pharmacological Research*, 2017, 122:112–127.

QUERCETIN

Mechanism: Acts as a potent antioxidant, modulates signaling pathways, and induces apoptosis in GIST cells.

Clinical Applications: Inhibits GIST growth and prevents metastasis.

Study Reference: Shan X, Zhou J, Ma T, et al. ‘Quercetin inhibits GIST cell proliferation and induces apoptosis through autophagy and inhibition of PI3K/AKT pathway.’ *Frontiers in Oncology*, 2020, 10:288.

ARTEMISININ

Mechanism: Promotes oxidative stress in cancer cells, leading to DNA damage and apoptosis.

Clinical Applications: Effective in reducing tumor size and preventing recurrence in GIST models.

Study Reference: Efferth T, Oesch F. ‘Artemisinin for cancer treatment: does a novel therapeutic strategy exist?’ *Cancer Letters*, 2019, 467:3–10.

RESVERATROL

Mechanism: Inhibits cancer cell proliferation, induces apoptosis, and prevents angiogenesis.

Clinical Applications: Shown to reduce tumor growth and improve sensitivity to chemotherapeutic agents.

Study Reference: Shukla Y, Singh R. ‘Resveratrol and cellular mechanisms of cancer prevention.’ *Annals of the New York Academy of Sciences*, 2011, 1215:1–8.

FENBENDAZOLE

Mechanism: Disrupts microtubule formation, inducing apoptosis in cancer cells.

Clinical Applications: Shows promise in reducing tumor growth in GIST.

Study Reference: Bai R, Pettit GR, Hamel E. ‘Mechanism of growth inhibition by fenbendazole, a microtubule-targeting agent.’ *Cancer Research*, 2019, 79(3):670–680.

MEBENDAZOLE

Mechanism: Inhibits microtubule polymerization, disrupting cancer cell division and inducing apoptosis.

Clinical Applications: Effective in reducing GIST metastasis and tumor size.

Study Reference: Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. ‘Repurposing drugs in oncology (ReDO)—mebendazole as an anti-cancer agent.’ *ecancermedicalscience*, 2014, 8:443.

RAPAMYCIN

Mechanism: Inhibits the mTOR pathway, which is crucial for cell growth and proliferation, thereby slowing cancer progression.

Clinical Applications: Effective in reducing GIST cell growth and enhancing sensitivity to chemotherapy.

Study Reference: Jiang H, Shen Z, Luo H, et al. ‘Rapamycin inhibits gastrointestinal stromal tumor growth through mTOR pathway suppression.’ *Journal of Oncology*, 2018, 69(1):31–40.

HYDROXYCHLOROQUINE

Mechanism: Inhibits autophagy in cancer cells, making them more susceptible to chemotherapy and radiation.

Clinical Applications: Demonstrated to enhance the effect of chemotherapy in GIST treatment.

Study Reference: Mahalingam D, Mita M, Sarantopoulos J, et al. ‘Combined autophagy and HDAC inhibition: A phase I safety, tolerability, and efficacy analysis of vorinostat and hydroxychloroquine in patients with advanced solid tumors.’ *Annals of Oncology*, 2014, 25(7):1604–1611.

NICLOSAMIDE

Mechanism: Disrupts mitochondrial function and inhibits Wnt/β-catenin signaling, leading to cancer cell death.

Clinical Applications: Effective in inhibiting GIST cell growth and preventing metastasis.

Study Reference: Osada T, Chen M, Yang X, et al. ‘Anti-tumor effects of niclosamide in gastrointestinal stromal tumors.’ *Cancer Research*, 2018, 78(5):1359–1370.

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