Here are the descriptions for each of those, IPI-504 is at #9
off the GIST support website, emerging therapies page:
gistsupport.org
1. AMN107 is a tyrosine kinase inhibitor (like Gleevec) designed to bind more tightly than Gleevec to the Bcr-Abl abnormal fusion protein responsible for chronic myeloid leukemia. AMN107 also binds KIT and PDGFRA proteins that are relevant to GIST, as shown by cell studies.
2. RAD001 from Novartis is an orally available derivative of the compound rapamycin, found over 30 years ago in soil bacteria from Easter Island (called Rapa Nui in the native language). First tried as an antifungal, it was later approved as an immunosuppressant for organ transplants, blocking the proliferation of cells that cause rejection. Studies in the 1970s hinted at potential anticancer properties, but research was slow.
Later, rapamycin was found to inhibit an important kinase that was named mTOR (mammalian Target Of Rapamycin), a signal transduction molecule, downstream from the KIT kinase pathway. The mTOR pathway plays a role in normal cellular growth, proliferation and survival. The hope is that some cancers dependent on an overactive mTOR pathway might respond to a safe inhibitor.
More recently, for Gastrointestinal Stromal Tumor (GIST) resistant to the KIT inhibitor Gleevec, the idea of trying Gleevec in combination with RAD001 to further block of the downstream mTOR kinase pathway was proposed for clinical trial investigation.
3. Sorafenib (formerly called BAY 43-9006, now brand-named Nexavar) is an oral multikinase inhibitor that blocks the RAF kinase and VEGF receptors 2 and 3 to target tumor cell growth and angiogenesis, as well as PDGFR-B, KIT, FLT-3, and RET. During 2005 it was in clinical trials for kidney cancer and melanoma. Nexavar was approved by the FDA for use against kidney cancer in December 2005.
4. Another rapamycin derivative, CCI-779, has been developed by Wyeth-AyerstLabs, the pharmaceutical division of American Home Products Corp. It also inhibits the mTOR kinase pathway.
Dasatinib (brand name Sprycel), formerly known as BMS-354823, has been developed by Bristol-Myers Squibb. It is a potent oral multi-kinase inhibitor that targets ABL, SRC, KIT, PDGFR, and other tyrosine kinases. It has achieved success in clinical trials for imatinib-resistant patients with leukemia. Dasatinib was approved by the FDA on 6/28/2006 for use in those patients with chronic myeloid leukemia or acute lymphoblastic leukemia who have developed resistance or intolerance to imatinib (Gleevec). You can read about Sprycel's FDA approval for leukemia at the FDA site.
Dasatinib is structurally unrelated to imatinib, possibly demonstrating a higher binding affinity to KIT, regardless of the conformation of the KIT activation loop. It inhibits KIT autophosphorylation and KIT-dependent activation of downstream pathways including RAS/MAPK, PI3K/AKT, and STAT3. Preclinical cell studies by Shah et al (2006) indicate that dasatinib may inhibit the KIT D816V mutation that is resistant to imatinib. Shah et al suggest dasatinib may therefore be useful in treating systemic mastocytosis. Additional preclinical studies by Schittenhelm et al (2006) indicate effectiveness against KIT activation loop mutations D816Y and D116F as well as D816V. Therefore, dasatinib may potentially be useful against imatinib-resistant GISTs harboring these certain activation-loop mutations.
5. MLN518 (formerly known as CT53518) is a novel, oral, small molecule drug specifically designed to inhibit type III receptor tyrosine kinases, including FLT3, PDGFR, and KIT. It is being developed by Millennium Pharmaceuticals.
MLN518 is being used in clinical trials against leukemias. It has not been tried against GIST to date. However, it has been mentioned as potentially being useful against GISTs with PDGFRA mutations of type D842V, for which imatinib does not work (Corless, Schroeder, Griffith et al, 2005). Because D842V is a mutation involving the intracellular kinase domain of PDGFRA, there may be potential for MLN518 to be active against the parallel KIT exon 17 mutations (involving the second kinase domain) that are resistant to imatinib.
6. Genasense (oblimersen sodium) is an antisense oligonucleotide drug (a drug that targets expression of specific proteins). It inhibits production of Bcl-2, a protein made by cancer cells that is thought to block apoptosis (programmed cell death). By reducing the expression of Bcl-2 in cancer cells, Genasense may enhance the effectiveness of current treatments in causing cancer cell death.
7. AMG 706 from Amgen is a potent, oral, multi kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by selectively targeting all known VEGF, PDGF, Kit and Ret receptors. A Phase I open label, two center, dose-escalation study was initiated to assess the safety, establish the maximum tolerated dose and generate pharmacokinetic profiles of oral AMG 706 of oral AMG 706. AMG 706 was generally well tolerated. Most adverse events were of mild to moderate severity and reversible. AMG 706 demonstrated favorable bioavailability and half life using a 125 mg dose. Once daily dosing generated sustained exposure sufficient to elicit effective tumor responses. At least half of the subjects with advanced metastatic cancer experienced disease stabilization while on AMG 706 therapy.
Phase ll trial to determine the safety and effectiveness of AMG 706 in patients with advanced GIST has started. Patients must have documented treatment with imatinib mesylate (Gleevec) at least 600mg daily for at least 2 months, but the disease has progressed on this treatment. There can be no previous exposure to AMG706 or other tyrosine kinase inhibitors of c-kit (except imatinib mesylate) or VEGF (vascular endothelial growth factor) type (e.g., SU11248, PTK787) or anti-VEGF antibody (Avastin). Amgen asks that patients call the Amgen Call Center (1-866-572-6436) for a pre screen to be directed to the closest center. The centers should not be called directly until the prescreen is completed at the Call Center.
8. PKC-412, under developmenet by Novartis, is an inhibitor of VEGFR, PDGFR and multiple protein kinase Cs. Protein kinase C (PKC) is a family of serine-threonine protein kinases that are involved in signal transduction pathways that regulate cellular growth factor, proliferation, and apoptosis.
Phase I/II clinical trials of the combination of imatinib mesylate and PKC-412 for the treatment of imatinib mesylate-resistant GIST are being carried out. The trial protocols utilize a combination of imatinib mesylate plus PKC-142, as many of the tumor cells may still be under control or slowed by imatinib. A favorable strong drug-drug synergism between imatinib mesylate and PKC-142 provide rationale for this ongoing trial. Trials are currently being conducted at:
9. IPI-504 is under development by manufacturer Infinity Pharmaceuticals. This drug targets Heat-shock protein 90 (Hsp90). Hsp90 is one of a class of chaperone proteins, whose normal job is to help other proteins acquire and maintain the shape required for those proteins to do their jobs. Chaperone proteins work by being in physical contact with other proteins. Hsp90 can also enable cancer cells to survive and even thrive despite genetic defects which would normally cause such cells to die. Thus, blocking the function of Hsp90 and related chaperone proteins may cause cancer cells to die, especially if blocking chaperone function is combined with other strategies to block cancer cell survival.
10. 17-AAG (17-allylamino, 17-demethoxygeldanamycin) is a molecule that inhibits the activity of a protein called HSP90 (heat shock protein 90). HSP90 is one of a class of proteins which are normally in cells and are produced in greater amounts when cells are stressed. In cancer cells, HSP90 in particular has enabled certain such cells to survive and even thrive. For instance, high levels of HSP90 in breast cancer cells is associated with poor prognosis, and HSP90 stabilizes KIT, the protein driving cancer cell survival and division in GIST.
11. Perifosine (KRX-0401) is a novel oral bioavailable phospholipid under development by KERYX Biopharmaceuticals. Phospholipids have displayed significant antiproliferative activity in several human tumor types through inhibition of the Akt protein. Akt appears to be activated by most anti-cancer therapies conferring cell survival and proliferation. The anti-Akt action of perifosine may enhance the effects of other treatment agents by promoting apoptosis and interfering with cell growth signals. It also appears to induce apoptosis through JNK activation.
12. Flavopiridol is a semisynthetic flavone (related to substances found naturally in plants). It acts as a cyclin-dependent kinase inhibitor, meaning that it inhibits progression of cells through the "cell cycle" leading to cell proliferation. [Cancer cells proliferate in an uncontrolled manner, thus causing tumor growth.] Flavopiridol also inhibits src kinases and survivin, and it transcriptionally represses expression of numerous genes. It has been studied in several Phase I and Phase II trials against various types of cancer. For a free-access paper describing some of the results, see Shapiro, 2004. Several Phase II trials have shown subsets of patients with prolonged stable disease.
Recently Sambol et al (2006) described preclinical (test tube) results using flavopiridol against GIST cell lines to see if it would prevent expression of KIT. This research group from Memorial Sloan Kettering Cancer Center found that flavopiridol could make GIST cells susceptible to apoptosis (cell death) by blocking the expression of KIT in the cells. This is a different strategy from imatinib (Gleevec), which blocks activation of KIT but does not reduce its expression in the cell. |
