Treatment+for+Metastatic+GIST

= Introduction of GIST = For our cancer project we studied gastrointestinal stromal cancer and more specifically, the progressive treatments of gastrointestinal stromal tumors (GIST). These are uncommon tumors of the GI tract that start in very early forms of special cells found in the wall of the GI tract, called the interstitial cells of Cajal (ICCs). ICCs are cells of the autonomic nervous system, the part of the nervous system that regulates body processes such as digesting food. More than half of GISTs start in the stomach. Most of the others start in the small intestine, but GISTs can start anywhere along the GI tract (1).The diameter of GISTs can range from a few millimeters to over 30 centimeters. And while larger tumors have a higher rate of malignancy, smaller tumors behave malignantly as well. The degree of malignancy of a GIST is based on how invasive the tumor is, locally and distally. GIST commonly metastasizes to the liver (11).

=//**Imatinib mesylate**//=

After the initial treatment of surgery, one drug, Gleevac, or imatinib, has been effective in the treatment of GIST. Originally used for CML treatment, Imatinib acts by occupying the kinase pocket of the BCR-ABL (a tyrosine kinase inhibitor) oncoprotein preventing the phosphorylation of its substrate (2). In other words, it is a kinase inhibitor that works to prevent the gain-of-funciton muation of c-KIT. Imatinib has proven to be a useful treatment of these tumors, however clinical responses to imatinib depended on the exonic location of KIT mutations in GIST, and only 10–20% of GIST patients exhibit primary resistance to imatinib (3). Table 2 tells us that the actual location of the mutation has a high correlation to the expected response from imatinib treatment and the corresponding survival rate as seen in Figure 1. (3) **Figure 1.** Gastrointestinal stromal tumor (GIST) kinase genotype correlates with event-free survival and overall survival. Kaplan-Meier estimate of the probability of event-free survival (A) and overall survival for all patients in the CSTI571B 2222 phase II GIST study (B). Kaplan-Meier estimate of the probability of event-free survival (C) and overall survival (D) for patients with //KIT// exon 11 mutation, //KIT// exon 9 mutation, or no mutation of //KIT// or platelet-derived growth factor receptor alpha (PDGFRA). The log-rank //P// value is listed above each graph (10). As seen in Table 2, some of these mutations have some to no response to imatinib treatment. If there is a mutation in exon 11 of KIT it is seen that the overall survival rate is nearly 100% (Panel D). However, in the case of GISTs with KIT exon 9 mutations or no kinase mutations, there is a lower chance of survival over a period of 800 days. Imatinib resistance is probably due to KIT mutations in tumor cells present before initiation of therapy. Specifically, these turnouts [?]  are thought to have a lesser dependence on KIT signaling for cellular proliferation and avoidance of apoptosis. Therefore, they can more easily adapt to conditions of KIT inhibition (5). In most cases, of those who have an initial response to the imatinib treatment and then continue with disease progression (secondary resistance), a secondary mutation in KIT (in addition to the primary oncogenic mutation) can be found, usually in the kinase domain, which leads to an imatinib-resistant KIT oncoprotein (3). These secondary mutations are believed to prevent imatinib from binding either by directly altering the pocket itself or by leaving the kinase in a "constantly on" conformation (imatinib can only bind when the kinase is inactive) (4).

Sunitinib is a recently approved therapy that is given to patients in this secondary resistance phase. Sunitinib has been shown to prolong survival, but its best response is generally just a stable disease (3). Due to the heterogeneous properties of the oncogene(s), the cancer is able to adapt to the presence of imatinib and find new ways to continue to grow. Efforts to manage this secondary stage of tumor growth can be seen with the approval of Sunitinib.
 * Figure 2.** The image on the left shows a GIST patient that has multiple liver metastases as signified by the arrows. The image on the right is the same patient after treatment with imatinib mesylate. As you can see in the images the tumors have significantly decreases in size with treatment (11).

=__//**Sunitinib malate**//__=

Sunitinib malate (Sutent) is a multi-targeted tyrosine kinase inhibitor that is used as a second-line therapy for patients who have developed a resistance or intolerance to imatinib. Sunitinib's multi-targeting abilities are advantageous due to its ability to target the surrounding tissue in addition to the tumor itself, and resistance is less likely to occur. Also, taking one multi-targeted drug is preferable to taking many single-targeted inhibitors because it decreases toxicity caused by drug-drug interactions. Sunitinib's multi-targeted features include anti-angiogenic and anti-tumor properties. By inhibiting angiogenesis and growth factor receptors, sunitinib has proven to be an effective GIST therapy(6). To prevent angiogenesis, sunitinib targets tyrosine kinase receptors VEGFR1, VEGFR2, and VEGFR3. VEGFR1&2 are associated with endothelial angiogenesis while VEGFR3 is associated with lymphangiogenesis(7). VEGFR1&2 inhibition would work on stopping angiogenesis within the tumor itself while VEGFR3 inhibition is important in cancer that has metastasized in the lymph nodes. Sunitinib works by binding to the tyrosine kinase receptors which prevents the vascular endothelial growth factors from binding and promoting angiogenesis. In angiogenesis in healthy tissue, it quickly becomes stable and growth stops. However, in cancerous tissue, angiogenic growth factors are over expressed causing rapid and continuous angiogenesis,allowing for tumor progression(6).


 * Figure 3.** Tyrosine kinase receptors involved in angiogenesis and lymphangiogenesis targeted by sunitinib. a) Singnaling through endothelial growth factor receptors (VEGFR1 and VEGFR2) and platelet-derived growth factor receptors (PDGFRs) leads to endothelial cell growth, and migration and survival. b)Tumor lymphangiogenesis is mainly driven through VEGFR3 and PDGFR signaling in tumor-associated macrophages and lymphatic endothelial cells. Activated macrophages facilitate the intravasation of tumor cells, thus aiding metastasis.

A two-armed, randomized, double-blind, placebo-controlled study of sunitinib was conducted to test the drug's efficacy as a GIST therapy. The patients enrolled in this trial either developed a resistance or intolerance to imatinib, or had disease progression while being treated with imatinib. The patients were randomized 2:1, given either 50 mg of sunitinib daily, or an oral placebo. 207 patients were in the sunitinib arm while 105 patients were randomized into the placebo arm. The demographics of the two arms were fairly even in regards to the age of the patients(69% vs 72% < 65 years for SUTENT vs. placebo, respectively), gender(Male: 64% vs. 61%), race(White: (88% both arms, Asian: 5% both arms, Black: 4% both arms, remainder not reported), and previous treatment including surgery(94% vs. 93%). Also comparable was the response rate to previous imatinib treatment among the two arms, with progression within the first 6 months imatinib treatment(17% vs. 16%), and progression after 6 months of treatment(78% vs. 80%). The data from the study was analyzed after 149 Time-to-Tumor Progression events had occurred(9). What they found was that the patients treated with sunitinib had a significantly longer median time to tumor progression which was 27.3 weeks, while the placebo's median time to tumor progression was 6.4 weeks. After the interim data analysis at 149 evens of TTP, the study was unblinded and the patients in the Placebo arm were given the chance to receive treatment. Ninety-nine patients, originally in the Placebo arm, chose to receive sunitinib. The final analysis of the study examined overall survival of the two treatment arms. The median overall survival for sunitinib was 72.7 weeks while the median overall survival for the placebo group was 64.9 weeks. The study does not specify if they included those patients that switched from Placebo to sunitinib in the sunitinib arm. However, due to the fairly long median overall survival for the placebo group, we would assume that the data from the patients that switched treatments was included in the placebo groups median overall survival. Because the researchers chose to conduct the study this way due to ethical reasons, that data on overall survival is not conclusive.
 * Figure 4. **Kaplan-Meier Curve of TTP in GIST Study A (Intent-to-Treat Population)

=__//**Regorafenib**//__=

One of the newest forms of treatment for GIST after imatinib and sumatinib fail to work is the drug regorafenib. Orally taken, this active multikinase inhibitor acts against various kinases including those involved in oncogenesis (KIT, RET, RAF1, BRAF and BRAF V600E), regulation of tumor angiogenesis (VEGFR1-3 and TEK), and the tumor microenvironment (PDGFR and fibroblast growth factor receptor).
 * Figure 5.** Mechanism by which Regorafenib inhibits VEGFR (Vascular endothelial growth factor receptor), PDGFR (Platlet driven growth factor receptor), KIT, and BRAF.(12)

In various preclinical models, regorafenib showed potent antitumor activity in the inhibition of growth of GIST cell lines, inhibition of tumor growth, and antimetastatic activity in several mouse xenografts (A surgical graft of tissue from one species to an unlike species, genus, or family). Because the phase I and phase II results were so promising, regorafenib moved to phase III where patients were placed either on regorafenib or a placebo. After 3 months, progression free survival rate of regorafenib was 60% while the placebo was 11%. At the end of 6 months, regorafenib was 38% and placebo was 0%. Because of these encouraging results and tolerable toxicity, the drug obtained FDA approval in February just last year for the treatment of metastatic or un-resectable GIST after failure or intolerance to imatinib and sunitinib (13).



**Figure 6.** Kaplan-Meier survival analysis after treatment with regorafenib or placebo (A) Progression-free survival, per central review (primary endpoint, final analysis). (B) Overall survival (interim analysis). HR=hazard ratio (14).

=Conclusion=

Imatinib mesylate is likely to continue being the primary therapy option for un-resectable GIST due to its proven efficacy of treating the most common mutation in GIST. A mutation of KIT at exon 11 and a mutation of KIT at exon 9 make up 85% of GIST cases, and imatinib is capable of treating both of these. However, for those patients who don't have a KIT mutation at exon 11 or exon 9 or are wild type, sunitinib is a second-line therapy. Due to its activity as a multi-targeted tyrosine kinase inhibitor, it not only inhibits the activity of KIT, but VEGFR1/2/3 and PDGFRs as well. The other receptors targeted by sunitinib receive vascular endothelial growth factors and platelet-driven growth factors which results in them promoting angiogenesis. The final drug, Regorafenib not only targets all the receptors that sunitinib targets, but it targets BRAF, RET, and RAF1 as well. Because it targets more receptors than sunitinib, it seems like regorafenib would be a better option as the second-line therapy. However, regorafenib was only approved in 2013. So, while regorafenib may prove to be a better second-line therapy in the future, there has not yet been a study comparing the efficacy of the two drugs against each other. But when comparing data of the two drugs found from separate studies the median progression-free survival is about the same. However, a very small percentage of GIST patients have the BRAF V600E mutation which only regorafenib is capable of treating. It will be interesting to see how the treatment of GISTs will expand and progress as more research is done.

Works Cited: 1. "What Are Gastrointestinal Stromal Tumors?" American Cancer Society N.p., n.d. Web. 05 June 2014. 2. Fletcher, Jonathan A., and Brian P. Rubin. "KIT Mutations in GIST." Current Opinion in Genetics & Development 17.1 (2007): 3-7. Web. 3. Hornick, Jason L., and Christopher D.M. Fletcher. "The Role of KIT in the Management of Patients with Gastrointestinal Stromal Tumors." Human Pathology 38 (2007): 679-87. ELSEVIER. Web. 4.Heinrich, Michael C. "Molecular Basis for Treatment of Gastrointestinal Stromal Tumours." EJC Supplements 4.1 (2006): 10-18. ELSEVIER. Web. 5. Silva, Chandu De, and Robin Reid. "Gastrointestinal Stromal Tumors (GIST): C-kit Mutations, CD117 Expression, Differential Diagnosis and Targeted Cancer Therapy with Imatinib." Pathology Oncology Research 9.1 (2003): 13-19. ELSEVIER. Web. 6. Faivre, Sandrine, George Demetri, William Sargent, and Eric Raymond. "Molecular basis for sunitinib efficacy and future clinical development." N.p., Sept. 2007. Web. 21 May 2014. <ftp://sogr.idv.tw/%AEa%B1%DA%C0%C9%AE%D7%B3%C6%A5%F7/%C4%AC%A4h%BB%A8/reference/1.pdf> 7. "Interactions of VEGF ligands and VEGF receptors." Biooncology. Genentech, 2014. Web. 21 May 2014. <http://www.biooncology.com/research-education/vegf/vegf/vegf-pathway/receptors>. 8. Younus, J., S. Verma, J. Franek, and N. Coakley. "Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate–resistant patients: recommendations and evidence." NCBI. N.p., Aug. 2010. Web. 21 May 2014. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913827/>. 9. "Sutent." RxList. N.p., 7 Oct. 2013. Web. 4 June 2014. <http://www.rxlist.com/sutent-drug/clinical-pharmacology.htm>. 10. Heinrich, Michael C. "Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor."American Society of Clinical Oncology (2003). <http://jco.ascopubs.org/content/21/23/4342.full.pdf>. 11. Nguyen, Vu H. "Imaging in Gastrointestinal Stromal Tumors - Leiomyoma/Leiomyosarcoma ." Medscape. N.p., 24 Sept. 2013. Web. 5 June 2014. <http://emedicine.medscape.com/article/369803-overview>. 12. http://www.bayerpharma.com/html/images/upload/Therapiegebiete/direkt_regorafenib_engl_large.jpg 13. <span style="background-color: #ffffff; font-family: Arial,Helvetica,sans-serif;">Serrano, Ceasar, and Suzanne George. "Recent Advances in the Treatment of Gastrointestinal Stromal Tumors." Therapeutic Advances in Medical Oncology. N.p., May 2014. Web 14. Demetri, George D. "Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3." The Lancet 381.9863 (2012): 295-302 <http://www.thelancet.com/journals/lancet/article/PIIS0140673612618571/abstract>. 15. http://artandcancer.com/category/%D8%A7%D9%86%D9%88%D8%A7%D8%B9-%D8%B3%D8%B1%D8%B7%D8%A7%D9%86/page/10/