For cancer treatment, the initial method of chemotherapeutic agents has been cytotoxic drugs. Their action of mitotic inhibition is not limited to cancer cells, particularly profound effects being seen on the haematopoietic system, often with resulting neutropenia or pancytopenia. What is targeted therapy for cancer? Targeted therapy is a newer type of cancer treatment that uses drugs or other substances to more precisely identify and attack cancer cells, usually while doing little damage to normal cells. It has been validated to be a curative treatment for various kinds of cancer, including prostate cancer, leukemia, lung cancer and pancreatic cancer.
A wide variety of targeted therapies are available for the treatment of kidney cancer. The identified targeted therapies work by disrupting specific signalling pathways involved in tumour progression, such as those responsible for angiogenesis and cell proliferation. Tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are now established classes of drugs used in the treatment of kidney cancer, with a many of them having received regulatory approval to date. such as sorafenib, sunitinib, pazopanib, axitinib, temsirolimus, and everolimus.
Tyrosine kinase inhibitors (TKIs) are small molecules that inhibit a variety of different signalling molecule receptors, including VEGFR-1, VEGFR-2, and VEGFR-3; PDGFR-α and PDGFR-β; c-RET; macrophage colony-stimulating factor (CSF-1R); FMS-like tyrosine kinase-3 receptor (Flt-3); and c-KIT. This activity provides them with the potential to disrupt a range of tumour angiogenesis signalling pathways.
Sorafenib is an orally active TKI that been shown to exhibit inhibitory effects against VEGFR-2 and VEGFR-3, PDGFR-β, Flt-3, RAF-1, and c-KIT.
Sunitinib is also an orally active TKI and has affinity for VEGFR-2, Flt-3, c-KIT, and PDGFR-β.
Pazopanib is orally active and has been shown to inhibit VEGFR-1, VEGFR-2, and VEGFR-3; PDGFR-α and PDGFR-β; and c-KIT.
Axitinib has been shown to be highly selective for inhibition of VEGFR-1, VEGFR-2, and VEGFR-3 over other compounds such as PDGFRs and KIT.
Tivozanib is an orally active TKI and, as with axitinib, has inhibitory activity against VEGFR-1, VEGFR-2, and VEGFR-3.
Dovitinib is an orally active TKI that has activity against VEGFR, FGFR, and PDGFR.
Regorafenib is an orally available TKI that is known to inhibit VEGFR-1, VEGFR-2, and VEGFR-3, as well as PDGFR-β, FGFR-1, Tie2, BRAF, RAF-1, and RET.
Cediranib has been shown to be highly potent in in vitro assays and pre-clinical models, inhibiting all three VEGF receptors.
Rapamycin was initially investigated as an immunosuppressant owing to its ability to inhibit T cell function for organ transplant patients. It was subsequently identified as having anti-proliferative effects in a number of malignancies. Rapamycin binds to the intracellular FK506 binding protein 12 (FKBP12), and the resulting protein–drug complex inhibits mTOR kinase activity. To date, there are two mTOR inhibitors that are approved for use in the treatment of advanced kidney cancer, temsirolimus, and everolimus.
Temsirolimus is a pro-drug of rapamycin that is rapidly metabolised in the liver by cytochrome CYP 4503A4/5 to the active form. It has better chemical stability and solubility than rapamycin does, making it suitable for intravenous administration.
Everolimus is an orally available hydroxyethyl ether derivative that does not require in vivo transformation to sirolimus in order to be active.
Colorectal cancer (CRC) is one of the most common cancers and the second leading cause of cancer worldwide. Approximately
25% of newly diagnosed patients have already developed metastases,and 50%of all colorectal cancer patients will develop metastases over time as the disease progresses. Systemic therapy was restricted to fluoropyrimidine (5-FU)-based regimens alone or in combination with oxaliplatin or irinotecan for many years.
Survival of patients with metastatic colorectal cancer (mCRC) has been significantly improved with the introduction of the monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Novel molecular-targeted agents such as aflibercept and regorafenib have recently been approved.
VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer.
Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting VEGF. On June 20, 2006, the FDA granted approval for a labeling extension for bevacizumab, administered in combination with intravenous 5-fluorouracil based chemotherapy, for the second-line treatment of metastatic carcinoma of the colon or rectum. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving bevacizumab plus FOLFOX4 (5-flourouracil, leucovorin, and oxaliplatin) when compared to those receiving FOLFOX4 alone.
Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin. As a VEGF inhibitor, it is approved for the treatment of colorectal cancer.
Regorafenib is an oral multi-kinase inhibitor developed which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Regorafenib demonstrated to increase the overall survival of patients with metastatic colorectal cancer and has been approved by the US FDA on September 27, 2012.
Epidermal growth factor receptor (EGFR) belongs to a family of receptors known as the ErbB family (ErbB tyrosine kinase receptors) which comprises four proteins encoded by the c-erbB proto-oncogene. EGFR is known to activate a cascade of multiple signaling pathways that facilitate tumor growth process. EGFR has been shown to be overexpressed in colorectal cancer patient populations. The development of a panel of EGFR inhibitors could reduce the proliferation of tumor cells when used alone or in combination with cytotoxic drugs or radiation.
Cetuximab, a chimeric IgG1 monoclonal antibody that binds to the extracellular domain of EGFR, blocks ligand-induced receptor signaling and modulates tumor-cell growth. Cetuximab has activity in colorectal cancer and can reverse drug resistance in patients with colorectal cancer when administered with irinotecan.
Panitumumab is a 100% human IgG2 anti-EGFR mAb developed using XenoMouse technology. Panitumumab was approved for monotherapy of relapsed/refractory mCRC by the US Food and Drug Administration in September 2006 and conditionally approved (in patients with tumours harbouring wild-type KRAS) by the European Medicines Agency (EMEA) in December 2007.
In May 2007, sorafenib was approved for "unresectable hepatocellular carcinoma (HCC), and was the first molecular targeted agent for use in liver cancer. Now many new agents are being developed and the combination therapy with sorafenib and standard treatment are being tried to conquer the liver cancer. The new agents includ mTOR inhibitors, Brivanib, Axitinib, E7080, CS1008 and many other agents.
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycine (mTOR) pathway also plays an important role in cell growth, survival regulation, metabolism and anti-apoptosis. Inhibiting mTOR with molecules, such as RAD001, generates additive effects that accompany upstream and downstream target inhibition; alternatively, upstream receptor inhibition is compensated for by inhibiting the downstream pathway, even if some resistance develops against receptor inhibition regardless of initial or acquired resistance. Therefore, RAD001 is a potential targeted agents for liver cancer.
The mTOR inhibitors includ everolimus (RAD001), sirolimus (Rapamune) and temsirolimus (CCI-779) and so on.
Brivanib is a kinase inhibitor that selectively inhibits VEGFR-1, -2 and -3, and FGFR-1, -2 and -3. So that the Angiogenesis can be inhibited, which is an important event not only for liver cancer but also for cancer growth and metastasis.
E7080 inhibits phosphorlation of growth factor receptors such as the VEGF receptor, KDR, Flt-1, FGFR1, and PDGFRβ-receptors that are important for angiogenesis. FGF and PDGF are potent promoters of tumor cellproliferation. With this action, E7080 is expected to exert its potent inhibition on tumor proliferation led by antiangiogenic effect with the inhibition of VEGF in addition to proliferation of tumor cells.
CS1008 is an agonistic agent to death receptor (DR) 5 or TNF-related apoptosis inducing ligand (TRAIL). In vitro nonclinical studies have shown that CS-1008 exhibits antitumor activity in DR5 positive tumor cells treated with CS-1008 and cross-linking with anti-human IgG antibody.CS-1008 was shown to induce apoptosis in DR5 positive tumor cells resulting in cell death.
Ovarian cancer is the most common cause of mortality of tumors fromgynecologic origin and is often diagnosed after patients have already progressed to advanced disease stage. The current standard of care for treatment of ovarian cancer includes cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately,many patients will recur and ultimately die from their disease. Targeted therapies have been evaluated in ovarian cancer as a method to overcome resistant disease.
Angiogenesis is the development of new blood vessels in areas of new tissue growth. It is also an important process that occurs almost universally in solid tumors as a response to the expansion of the cancer mass. Molecular markers of angiogenesis have been studied in ovarian cancer. It is found the importance of the VEGF pathway in angiogenesis. Bevacizumab is a monoclonal antibody directed against VEGF-A. Researches and clinical trials have been made and apparent responces have been revealed.
Epidermal growth factor receptor (EGFR) is overexpressed in 70% of cancers and is associated with chemoresistance, poor prognosis, and advanced disease at presentation. The mechanism of growth factor receptors is via activation of the intracellular tyrosine kinase domain, which triggers downstream targets and subsequently cell proliferation and survival. Preclinical studies suggested that inhibiting this target might reverse chemoresistance and demonstrate antitumor activity. Unfortunately,clinical trials evaluating drugs affecting these pathways, such as studies of EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) and monoclonal antibodies directed against EGFR (cetuximab, panitumumab, and matuzumab), have not been met with significant success, showing only modest efficacy.
Sorafenib is an oral multikinase inhibitor that targets the mitogen-activated protein kinase (MAPK) pathway or Raf/MEK/ERK pathway. This drug also inhibits VEGFR- 1, -2, and -3 and platelet-derived growth factor receptor (PDGFR) beta tyrosine kinase activity. Sorafenib is currently FDA-approved for treatment of advanced renal cell cancer, and the biologic rationale for attempting its use in other solid tumors is the fact that MAPK pathway is well conserved evolutionarily and may serve as a central and common target.
Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in repair of DNA single-strand breaks using the base excision repair pathway. A recent review by Yap et al. detailed the mechanism by which PARP inhibition can lead to cancer cell death. Inhibition of PARP leads to the accumulation of DNA single-strand breaks, which may subsequently lead to DNA double-strand breaks at replication forks. In normal cells, double-strand breaks would be repaired in part by error-free homologous recombination DNA repair mechanisms. Olaparib is an oral small-molecular PARP inhibitor. A randomized phase II trial comparing olaparib (200 or 400 mg orally twice daily) with pegylated liposomal doxorubicin (50mg/m2 monthly intravenous) in patients with BRCA-mutated ovarian cancer with a platinum-free interval of 0–12 months is currently underway (NCT00628251).
Molecular targeted therapies have shown promise in the management of various malignancies, including melanoma, with lower toxicity profiles and better overall survival as compared with conventional therapy. The discovery of BRAF mutations in melanoma led to the development of BRAF inhibitors for the targeted therapy of advanced melanoma. However, growing concerns over drug resistance to molecular targeted therapies including BRAF inhibitors, have spurred efforts to elucidate additional molecular targets for the treatment of advanced melanoma.
In 2011 the US Food and Drug Administration approved the selective inhibitor of BRAF, vemurafenib, for patients with malignant melanoma bearing the activating BRAF (V600E) mutation. In a Phase I trial, 81% of patients with V600E-positive metastatic melanoma responded to treatment. Overall, 26 of 32 patients showed a partial response (defined as a decrease by at least 30% in the sum of the largest diameter of each target lesion), including two with complete resolution. Dabrafenib is another selective BRAF inhibitor that has shown significant activity in patients with metastatic melanoma in Phase I/II studies. Further clinical trials are underway with dabrafenib. It is important to note that the BRAF inhibitors, vemurafenib and dabrafenib, are the first treatments to show benefit in patients with metastasis to the brain. In addition, while vemurafenib has been studied in patients with the V600E mutation, studies with dabrafenib are examining activity in non-V600E and V600K mutations.
With limited disease-free survival rates and drug resistance following treatment with BRAF inhibitors, additional treatment options are needed. Efforts are underway to find other targeted therapies within the MAPK pathway that could be used alone or in combination with BRAF inhibitors. There has been significant investigation into MEK inhibition. Phase III trials comparing trametinib, a MEK inhibitor, with chemotherapy in patients with BRAF V600E/K mutant malignant melanoma show improved overall survival and progression-free survival. The combination of dabrafenib and trametinib has shown improved progression-free survival as well as reduction in the rate of secondary cutaneous neoplasms (such as squamous cell carcinoma). Based on the numerous pathways for resistance, MEK inhibition alone is unlikely to be the only answer to BRAF resistance. Nonetheless, MEK inhibitors have shown promise.
Another option being explored for targeted therapy in melanoma is the receptor tyrosine kinase, c-KIT (or CD117). Activating c-KIT mutations have been reported in approximately 20%–30% of certain subtypes of melanoma, including acral melanomas and mucosal melanomas, and melanomas that develop on photodamaged skin. The most common point mutation is L576P in exon 11, but point mutations also occur in exons 13, 17, and 18. Other tumors, including gastrointestinal stromal tumors with c-KIT mutations have been responsive to the tyrosine kinase inhibitor, imatinib. Therefore, Phase II trials were conducted with imatinib in patients with acral or mucosal melanoma or melanomas on chronically sun-damaged skin that harbored KIT mutations or amplifications. Response rates of 16%–23% with a small number of complete long-term responses have been seen, with no difference in response rates between the various melanoma subtypes.
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