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Targeted cancer therapies
- 1. Increased response togrowth signals Evasion of apoptosis Insensitivity to anti-growth signals Limitless replication potential Sustained angiogenesis Tissue invasion and metastasis 25-08-2016 1
- 2. Aberrant growth factor receptors Dysregulatedintracellular signalling pathways Defective DNA repair & apoptosis Tumour angiogen esis 25-08-2016 2
- 3. Achilles’ heel thatthe therapist can attack 25-08-2016 3
- 4. Targeted cancer therapies Dr. PoojaVaidya (Second year Resident) Guide: Dr. Sandhya Kamat Professor Dept. of Pharmacology & Therapeutics 25-08-2016 4
- 5. “Targeted cancer therapiesare drugs that interfere with specific molecular structures implicated in tumor growth and progression” 25-08-2016 5
- 6. Targeted cancer therapies Targetingnuclear factors Targeting cell survival Targeting angiogenesis Targeting cellular proliferation 25-08-2016 6
- 7. Primary tools fortargeted therapy Monoclonal antibodies Small synthetic molecules 25-08-2016 7
- 8. ABL – BCRkinase inhibitors EGFR inhibitors VEGFR inhibitors Multi-targeted TK inhibitors Drugs targeting nuclear receptors mTOR inhibitors Other kinase inhibitors Monoclonal antibodies Combination therapies Targeted cancer therapies 25-08-2016 8
- 9. Monoclonal antibodies • Blockcell surface receptors • Can carry toxins and radionuclides to the cells of interest thereby enhancing their cytotoxic effects • Specific for a single receptor • Long plasma half life • Intermittent administration Small molecules • May also exert effect by entering cells and inhibiting enzymatic functions • May inhibit multiple enzymatic sites • Half life is 12 – 24 hours • Daily administration 25-08-2016 9
- 10. 518 Protein kinases 91Protein tyrosine kinases (PTKs) Serine/threonine kinases & others Eg: TGF-β, RAF, ERK, MEK, Cyclin dependent kinases 59 Receptor PTKs 32 Non receptor PTKs Eg. ABL, JAK Trans membrane glycoproteins Eg: ErB family of receptors, PDGFR Targeted cancer therapies 25-08-2016 10
- 11. Imatinib mesylate Firstmolecularly targeted protein kinase inhibitor to receive FDA approval in 2003 Targets the BCR-ABL tyrosine kinase in a closed or inactive configuration 25-08-2016 11
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- 13. To overcome theresistance to Imatinib binds to multiple states of kinase including active conformation targets both ABL & SRC kinases active against almost all of the clinically relevant mutants, the exception being the T315I mutant more potent and less toxic than Imatinib Target the active kinase conformation Target substrate binding site ON012380 Dasatinib & Nilotinib Effective against all mutants including T315I Synergises well with Imatinib 25-08-2016 13
- 14. Imatinib, Dasatinib &Nilotinib Additional therapeutic benefits in, GIST ( kit mutation positive) Chronic myelomonocytic leukemia Hypereosinophilia syndrome Dermatofibrosarcoma protuberans Dose: Imatinib: 250 – 750mg/day Dasatinib: 100 mg daily (chronic CML) 70 mg BD (advanced CML) Nilotinib: 400 mg twice daily Bioavailability of Nilotinib increases in the presence of food ADR: Fluid retention & hepatotoxicity Dasatinib may cause pleural effusions Nilotinib may prolong the QT interval25-08-2016 14
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- 17. Gefitinib and Erlotinib Responsive tumors have specific activating mutations in the EGFR kinase domain which convert EGFR into a strongly oncogenic form that can be an essential tumor survival factor Act by targeting tumor survival factors Standard dose of Gefitinib is 250 mg daily In 2003, Gefitinib was approved for the third-line treatment of patients with NSCLC, but, two large trials have failed to demonstrate significant survival benefit But, Gefitinib continues to be widely used outside the U.S Both metabolized by CYP3A425-08-2016 17
- 18. Erlotinib isapproved for, Second-line treatment of patients with locally advanced or metastatic NSCLC (150 mg daily ) First-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine (100 mg daily ) Food increases bioavailability of Erlotinib to 100%, so should not be taken with food Concurrent PPI decreases the bioavailability of Erlotinib by 50% ADR: Diarrhoea , pustular/papular rash Asymptomatic increases in liver transaminases Interstitial lung disease in <2% cases but may have a fatal outcome. Gefitinib and Erlotinib 25-08-2016 18
- 19. Resistance to Gefitiniband Erlotinib 25-08-2016 19
- 20. Cetuximab & Panitumumab Cetuximab:recombinant chimeric human/mouse IgG1 antibody Panitumumab: recombinant, fully humanized IgG2 antibody Bind to extracellular domain of EGFR, blocking cell growth and survival signals Cetuximab Panitumumab 25-08-2016 20
- 21. Cetuximab is FDAapproved for, locally or regionally advanced HNSCC EGFR-positive metastatic colorectal cancer Single loading dose of 400 mg/m2 I.V. followed by weekly doses of 250 mg/m2 Panitumumab FDA approved as, First-line therapy in combination with FOLFOX in patients with wild-type KRAS mCRC Based on improved OS of 4.4 months in phase 3 PRIME study Dose: 6 mg/kg intravenously given once every 2 weeks ADR: Acne form rash, headache, and diarrhoea Cardiopulmonary arrest, interstitial lung disease, and hypomagnesemia Cetuximab & Panitumumab 25-08-2016 21
- 22. ErbB2 or HER2/neu inhibitors First mab approved for solid tumor Currently approved for HER2/neu-overexpressing metastatic breast cancer, in combination with paclitaxel as initial treatment or as monotherapy following chemotherapy relapse Most serious toxicity is cardiac failure Trastuzumab Lapatinib Blocks both ErbB1 and ErbB2 Inhibits the truncated form of HER2 that lacks the trastuzumab binding domain FDA-approved for HER2- amplified, trastuzumab- refractory breast cancer, with capecitabine Crosses the BBB ADR: Diarrhoea, rash25-08-2016 22
- 23. Targeting angiogenesis Judah Folkman:opened the field of anti-angiogenesis therapy Jain: proposed an additional mechanism, Capillary permeability and tumor interstitial pressure Inhibition of blood flow and drug delivery within the tumor Targeting primary angiogenic factor would normalize interstitial pressure & improve blood flow Enhance the ability of chemotherapeutic agents to reach the tumor 25-08-2016 23
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- 25. Bevacizumab FDA approvedfor, mCRC with combination chemotherapy First-Line Treatment of NSCLC in combination with carboplatin and paclitaxel Metastatic RCC in combination with interferon- alpha As a single agent following prior therapy for GBM Recurrent, or metastatic cervical cancer in combination with paclitaxel Doses vary reflecting the designs of approval directed trials Plasma t1/2: 4 weeks ADR: Risk of bleeding, hypertension, proteinuria, arterial thromboembolic event, GI perforation 25-08-2016 25
- 26. Sunitinib and Sorafenib Multi-targeted tyrosine kinase inhibitor Targets tyrosine kinase domain on the VEGFR-2, FLT3, PDGFR-α, PDGFR- β , RET, CSF-1R, and c-KIT Sunitinib approved for treatment of advanced renal-cell carcinoma and Imatinib resistant GIST 50 mg once a day for 4 weeks followed by 2 weeks off treatment Metabolized by CYP3A4 and t1/2 is 80 - 110 hours Sorafenib is the only drug currently approved for treatment of hepatocellular carcinoma Also approved in metastatic renal-cell cancer 400 mg twice daily without treatment breaks Metabolized by CYP3A4 and t1/2 is 20 - 27 hours 25-08-2016 26
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- 28. PI3K/PKB(Akt) /MTOR inhibitors FDA approved Temsirolimus and Everolimus for Renal cancer Dose: Temsirolimus 25 mg/week IV Everolimus 10 mg/day oral Administered in the fasting state at least 1 hour before a meal Also, implicated in, Hepatocellular cancer Mantle cell lymphoma Endometrial cancer Metabolized by CYP3A4 Toxicity: maculopapular rash, mucositis, anemia, and fatigue 25-08-2016 28
- 29. Mitogen-activated protein kinase(MAPK) pathway PD325901 AZD6244 (II) GSK1120212 (I) PLX4032 (III) GSK2118436 (I) 25-08-2016 29
- 30. Other kinase inhibitors DrugTarget Disease Clinical trial stage Other potential indications Crizotinib (PF02341066 ) ALK Lung cancer (EML4-ALK fusion) Phase 3 Anaplastic lymphoma, neuroblastoma, Inflammatory myofibroblastic sarcoma Vandetanib, Sorafenib, Motesanib RET Thyroid cancer Phase 3 Midostaurin AC220 FLT - 3 FLT mutant Acute myeloid leukaemia Phase 3 FLT mutant ALL INCB018424 TG101348 JAK-2 Myelofibrosis Phase 3 Phase 2 Polycythemia vera Essential thrombocytosis Axitinib Tivozanib Pazopanib VEGFR Renal cancer Phase 3 Hepatocellular carcinoma 25-08-2016 30
- 31. Targeting nuclear factors:Bortezomib NF-κB: tumor survival factor in hypoxic environment and during chemotherapy Blocks ubiquitin proteasomal protein degradation pathway, thereby preventing the transcriptional activity of NF-κB and down regulating survival responses FDA approved as initial therapy for Multiple Myeloma and as therapy for MM after relapse from other drugs for relapsed or refractory mantle cell lymphoma Dose: 1.3 mg/m2 I.V. bolus on days 1, 4, 8, and 11 of every 21- day cycle with a 10-day rest period per cycle Plasma t1/2: 5.5 hours Toxicity: Pancytopenia, fatigue, peripheral neuropathy, hypotension 25-08-2016 31
- 32. Targeted Anticancer TherapiesUsing Antibodies Monoclonal antibodies have become a major strategy in clinical oncology Specifically bind to primary and metastatic cancer cells with high affinity Antitumor effects by complement mediated cytolysis and antibody-dependent cell-mediated cytotoxicity (naked antibodies) By the focused delivery of radiation or cellular toxins (conjugated antibodies) 25-08-2016 32
- 33. Targeted Anticancer TherapiesUsing Antibodies 25-08-2016 33
- 34. Generic name Target; Format IndicationEU approval US approval Rituximab CD20; Chimeric IgG1 NHL 1998 1997 Trastuzumab HER2; Humanized IgG1 Breast cancer 2000 1998 Gemtuzumab ozogamicin CD33; Humanized IgG4 AML NA 2000 ## Alemtuzumab CD52; Humanized IgG1 CLL Multiple sclerosis 2001 ## 2013 2001 ## 2014 Ibritumumab tiuxetan CD20; Murine IgG1 NHL 2004 2002 Tositumomab - I131 CD20; Murine IgG2a NHL NA 2003 ## Approved Monoclonal antibodies 25-08-2016 34
- 35. Approved Monoclonal antibodies Generic name Target;Format Indication EU approval US approval Cetuximab EGFR; Chimeric IgG1 Colorectal cancer 2004 2004 Bevacizumab VEGF; Humanized IgG1 Colorectal cancer 2005 2004 Panitumumab EGFR; Human IgG2 Colorectal cancer 2007 2006 Ofatumumab CD20; Human IgG1 CLL 2010 2009 Ipilimumab CTLA-4; Human IgG1 Metastatic melanoma 2011 2011 Brentuximab vedotin CD30; Chimeric IgG1; Immunoconjugate Hodgkin lymphoma 2012 2011 25-08-2016 35
- 36. Approved Monoclonal antibodies Genericname Target; Format Indication EU approval US approval Pertuzumab HER2; humanized IgG1 Breast Cancer 2013 2012 Ado- trastuzumab emtansine HER2; humanized IgG1; Immunoconjugate Breast cancer 2013 2013 Obinutuzumab CD20; Humanized IgG1; Glycoengineered CLL 2014 2013 25-08-2016 36
- 37. Monoclonal antibodies inreview Generic name Target; Format Indication EU approval US approval Ramucirumab VEGFR2; Human IgG1 Gastric cancer Pending 2014 Pembrolizumab PD1; Humanized IgG4 Melanoma In review 2014 Nivolumab PD1; Human IgG4 Melanoma In review 2014 Blinatumomab CD19, CD3 ALL In review 2014 Necitumumab EGFR; Human IgG1 NSCLC In review In review 25-08-2016 37
- 38. Target and drugevaluation Target validation Appropriate preclinical models Desired target is known to be expressed Target is important for cell/ tumour survival In - vitro screening In - vivo models a cancer cell line /genetically engineered cell line Lead compound tested for target inhibition Confirmed by biochemical studies Xenograft model in immunocompromised mice Orthotopic grafts: metastatic cancer Transgenic models25-08-2016 38
- 39. Combination therapies Totarget the cancer stem cells Eg: Interferon + Imatinib for CML To target several different pathways that affect tumor growth Eg: Erlotinib and Bevacizumab in RCC Targeted inhibition can sensitize cancers to chemotherapy and radiotherapy Eg: Trastuzumab + chemotherapy in breast cancer 25-08-2016 39
- 40. 25-08-2016 40 Take homemessage… Molecularly targeted therapy is a new way of approaching cancer treatment Involves rational selection of drugs which target specific processes in cancer cells that make them different from normal cells A number of targeted therapies are currently available and many others are in development Targeted therapies are frequently effective but there are side effects to the treatments, and development of resistance Targeted therapies are increasingly being used in combination with other targeted therapies or with other treatment modalities
- 41. The Future IsNow: Pharmacogenomics and Personalized Medicine Personalized treatment using genomic or proteomic techniques To determine the most susceptible molecular targets in a specific patient To predict the likelihood that a patient will respond to a specific chemotherapy regimen To predict the risk of toxic side effects 25-08-2016 41
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Editor's Notes
- #2 What Makes Cells Cancerous?... All cancers acquire the same six hallmark capabilities… In some cases, a particular mutation may confer several capabilities (e.g., P53, the guardian of the genome may undergo mutation and cause resistance to apoptosis), whereas in other cases, multiple mutations may be required to enable a single capability.
- #3 Many new anti-cancer drugs recently approved or in late stages of evaluation are designed to block the fundamental mutations that cause specific cancers…like.. Those resulting in aberrant growth factor receptors, defective DNA repair and Apoptosis, Dysregulated intracellular signalling pathways and Tumour angiogenesis. Now, in case of signalling pathways ….
- #4 In normal cells, when one pathway is inhibited, the effect on the cell is minimized by the presence of alternative, redundant pathways. Whereas, cancer cells are particularly sensitive to inhibition of their overexpressed or hyper activated signaling protein. And Redundancy is reduced in cancer cells, owing to the large number of mutations that these cells sustain. Thus, cancer cell survival and proliferation depend on a few hyperactive signaling pathways, an Achilles’ heel that the therapist can attack Currently …we are shifting from a “black box” approach to specific, targeted therapy for the treatment of cancer And thus …the importance of targets in cancer treatment…and this forms the premise for TCT.
- #5 So, today… i will be talking on Targeted cancer therapies.
- #6 Every cell in the body contains 30,000 genes. Each of these genes makes a different protein and each protein performs a different task. Targeted therapies stop specific proteins from helping cancer survive. When certain specific proteins are blocked, the cancer cells can’t grow and they die. Thus, TCT are drugs that …..
- #7 The main strategies to achieve this ..is by targeting cellular proliferation, …..
- #8 The primary tools for inhibiting these targets are either monoclonal antibodies that attack cell surface receptors and antigens, or synthetic small molecules that enter cells and engage critical enzymes.. But, now, the point to be noted is that.. The two classes of drug, when targeted against the same pathway, may have significantly different spectra of antitumor activity. As shown in the figure here, monoclonal antibodies to the epidermal growth factor receptor (EGFR) are effective in the treatment of head and neck and colon cancers, while small molecules against the intracellular tyrosine kinase function of the same receptor have a different spectrum of antitumor activity in non–small cell lung cancer..
- #9 Now, For the purpose of discussion, I have classified the targeted cancer therapies based on the predominant target on which they act Structurally and functionally different molecules, may act on the same target and will be described based on the predominant target in my discussion.
- #10 The basic difference between these two classes of drugs are.. Small molecules may attack the same targets and pathways as the monoclonals, but may also exert their effect by entering cells and inhibiting enzymatic functions
- #11 Recognizing the families of proteins.. involved in the initiation, progression, and spread of cancer enables us to think rationally about which pathways to manipulate in order to suppress the disease. And.. the most popular candidates for targeted therapy are protein kinases. PKs control the balance between cell cycle progression, cell cycle arrest, and cell death and have been implicated in cancer. The human genome includes about 518 PKs. 91 of these are protein tyrosine kinases (PTKs), and others include Serine/Threonine kinase and others. Eg: TGF beta kinase, RAF kinase, MEK kinase, ERK kinase etc… PTK comprise of 59 receptor PTKs (RPTKs) and 32 non receptor PTKs. RPTKs are trans membrane glycoproteins Eg: ErB family of receptors, PDGF R. NR PTK’s ..Eg: ABL, JAK ERK: Extracellular signal – regulated kinase RAF: Rapidly Accelerated Fibrosarcoma MEK/MAPK: Mitogen activated protein kinase ABL: Abl stands for "Abelson", the name of a virus which carries a similar protein.
- #12 Imatinib received fast-track approval by the FDA as an ATP-competitive selective inhibitor of bcr-abl Imatinib bind to a segment of the bcr-abl kinase domain that fixes the enzyme in a closed or non functional state, in which protein is unable to bind ATP, thereby inhibiting the signalling pathway. One important point to be noted is that Imatinib is an inhibitor of the closed, or inactive, configuration of the kinase. Also, later it was realized that BCR‐ABL kinase is the major survival element in the leukemic cells in early phase CML. This is not the case for more advanced disease. So, Only a temporary effect was seen with Imatinib in acute CML, with disease recurrence in a matter of months Imatinib does not eradicate CML, relapse occurs if treatment is stopped Therefore, patients are now kept on Imatinib indefinitely, unless resistance emerges
- #13 A number of mechanisms of resistance to Imatinib have been characterized, the most common being mutations in the ABL kinase domain. The mutations lock the enzyme in its open configuration, in which it has access to substrate Other mechanisms of resistance include amplification of the BCR‐ABL gene, activation of BCR‐ABL independent alternative oncogenic pathways like the SRC signalling pathway.. And other minor mechanisms like presence of multidrug resistant (MDR ) gene which codes for a drug efflux protein. The realization of resistance lead to development of new targets …
- #14 To overcome resistance, new drugs were tested that can bind both active and inactive forms of the kinase and Dasatinib & Nilotinib were developed. less toxic.. because the active state of enzyme is present only transiently in healthy cells, whereas it is the predominant form of the enzyme in the targeted cancer cells. Also, being a dual Src‐Abl inhibitor such as Dasatinib provides “combination” therapy in a single formulation. Now, most current PTK inhibitors, including Imatinib, are ATP competitive inhibitors. But they tend to be poorly selective and target several related kinases. Another way to overcome resistance is targeting the substrate binding site. Recently, a substrate‐competitive inhibitor of BCR‐ABL, ON012380 has been developed. T315I mutant wherein Threonine is replaced by isoleucine at 315 position
- #15 These Tyrosine kinase inhibitors have efficacy in diseases in which the ABL, kit , or PDGFR have dominant roles in driving the proliferation of the tumor. Remarkable therapeutic benefits also seen in patients GIST ( kit mutation positive), chronic myelomonocytic leukemia (EVT6-PDGFR translocation), hypereosinophilia syndrome (FIP1L1-PDGFR), and dermatofibrosarcoma protuberans (constitutive production of the ligand for PDGFR) Food does not change the pharmacokinetic profile of Imatinib & Dasatinib... but.. All three drugs promote fluid retention, which may lead to dependent edema, and peri-orbital swelling
- #16 The EGFR family comprises four members: EGFR (ErbB1), ErbB2 (Her‐2), and ErbB4 have catalytic activity; ErbB3 is catalytically inactive but retains ligand binding. Ligand binding to the extracellular domain stimulates the protein tyrosine kinase activity of the intracellular domain which initiates protein-protein interactions that result in stimulation of a variety of signaling pathways Overexpression and/or abnormal activation of EGFR family members is associated with a wide spectrum of solid tumors, including non‐small cell lung carcinoma, breast cancer, pancreatic cancer, colon cancer, glioblastoma and head and neck cancer
- #17 Two separate classes of drugs that target the EGFR pathway have become important agents in the therapy of solid tumors. Small molecules ie. The EGFR tyrosine kinase inhibitors erlotinib and gefitinib bind to the kinase domain and block the enzymatic function of EGFR. The monoclonal antibodies cetuximab and panitumumab bind specifically to the extracellular domain of EGFR.
- #18 EGFR is overexpressed in over 80% of NSCLC, so it was hoped that drugs like Gefitinib would have a major impact on treatment of the disease. But these hopes were shattered when only 10% of NSCLC patients responded to Gefitinib in clinical trials in the United States. The frequency of response to Gefitinib was higher among women, non-smokers, and East Asians. Then it was found that the responsive tumours… New clinical trials are being developed, other ongoing trials are being completed. These will determine the future role of Gefitinib treatment. But, Gefitinib continues to be widely used outside the U.S Diarrhea and pustular/papular rash occur in ~50% of patients taking gefitinib
- #19 Second-line treatment of patients with locally advanced or metastatic NSCLC (based on improvement in overall survival in a large multi-national trial comparing oral Erlotinib, 150 mg daily, to placebo) First-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine (based on a double-blinded study of 569 patients which demonstrated a modest 2-week improvement in overall survival in patients who received 100 mg of erlotinib plus gemcitabine, as compared with patients who received gemcitabine alone)
- #20 But, Resistance to Gefitinib and Erlotinib arises through several different mechanisms A secondary mutation in the EGFR gatekeeper residue, T790M, prevents binding of drug to the kinase domain and confers resistance. Irreversible EGFR inhibitors currently are in clinical development to overcome this mechanism. Amplification of the met oncogene provides an alternative pathway to clinical resistance by activating cell growth signals downstream of EGFR. Such MET -amplified tumors respond in vitro to the simultaneous inhibition of EGFR and MET in combination therapies
- #21 Both bind to extracellular domain of EGFR & prevents ligand dependent signalling and receptor dimerization, thereby blocking cell growth and survival signals. Cetuximab is fda approved for metastatic colorectal cancer, but, numerous trials now have shown that the 40-50% of colorectal tumors carrying mutations in the k-ras oncogene are resistant to the effects of cetuximab. The antibody yields a response rate of 1% in patients with mutant tumors, compared to 12% in k-ras wild-type tumors mCRC: metastatic colorectal cancer
- #22 HNSCC: squamous cell carcinoma of head & neck region
- #23 In this case, both monoclonal antibody trastuzumab and small molecules lapatinib have striking antitumor effects in patients with HER2-positive breast cancer, and have become essential therapeutic agents. Trastuzumab was the first monoclonal antibody to be approved for the treatment of a solid tumor. This humanized Mab binds to the external domain of HER2/neu, thereby preventing receptor kinase activation and downstream signaling and blocks of the angiogenic effects of HER2 signaling. Currently, it is approved for HER2/neu-overexpressing metastatic breast cancer, in combination with paclitaxel as initial treatment or as monotherapy following chemotherapy relapse. The most serious toxicity of trastuzumab is cardiac failure; reasons for cardio toxicity are poorly understood. Lapatinib: block both ErbB1 and ErbB2. 2 main advntages of Lapatinib are, It inhibits the truncated form of HER2 that lacks the trastuzumab binding domain, responsible for activity in trastuzumab resistant patients. FDA-approved for HER2-amplified, trastuzumab-refractory breast cancer, in combination with capecitabine. Being a small molecule, lapatinib crosses the blood-brain barrier more readily than inhibitor antibodies and has produced anecdotal responses in patients with brain metastases ADR: Diarrhoea, rash, no cardio toxicity noted with its use.
- #24 he hypothesized that angiogenesis-is an essential property of cancer. Cancer cells secrete angiogenic factors like VEGF , FGF , TGF- β , PDGF that induce the formation of new blood vessels and guarantee the flow of nutrients to the tumor cells. Multiple tumor types overexpress these angiogenic factors. Jain has proposed an additional mechanism for the efficacy of angiogenesis inhibitors. Increased capillary permeability within tumors cause an increase in tumor interstitial pressure. Increased pressure inhibits blood flow, decreases oxygenation, and prevents drug delivery within the tumor. Antibodies directed at the primary angiogenic factor normalize interstitial pressure, improve blood flow. Enhance the ability of chemotherapeutic agents to reach the tumor
- #25 The best studied of the angiogenic factors is VEGF. VEGF receptor family includes VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). The binding of VEGF to its receptor activates the intracellular VEGFR tyrosine kinase activity and initiates mitogenic and anti-apoptotic signaling pathways. The cognate interaction between VEGF and its receptor creates several opportunities for pharmacological inhibition of this pathway. Bevacizumab humanized antibody directed against VEGF-A, is the first FDA-approved molecule that specifically targeted angiogenesis. Small molecules ( sorafenib, and sunitinib) that inhibit the kinase function of VEGFR-2 have been approved for clinical use Also, an investigational drug Aflibercept , is a recombinant fusion protein that combines VGFR-1 & VGFR-2 binding domains with Fc region of human IgG1 antibody to sequester VEGF-A, therby acting as acts as VEGF Trap… available with the brand name..Zaltrap !!
- #26 Recently in 2014, US FDA approved Bevacizumab for the treatment of persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel. The differing doses of bevacizumab reflect the varying designs of approval-directed trials. The most dreaded vascular toxicity of anti-angiogenic agents is an arterial thromboembolic event (i.e., stroke or myocardial infarction. A meta-analysis found that the rate of arterial thromboembolic events in patients receiving bevacizumab-containing regimens reached 3.8% compared to the control rate of 1.7%
- #27 Sunitinib is approved for treatment of advanced renal-cell carcinoma and GIST that have developed resistance to imatinib as a consequence of c-KIT mutations CSF-1R: Colony stimulating factor -1 receptor
- #28 The phosphatidyl inositol (PI-3) kinase pathway is central to intracellular signalling. PI3-kinase,a type of receptor tyrosine kinase, is activated by many growth factor receptors and leads to the formation of the intracellular messenger PIP3. And the downstream effectors, the mechanistic target of rapamycin (mTOR) modulates cell growth, metabolism, and apoptosis. The tumor suppressor PTEN dephosphorylates PI3K. Activating mutations and amplification of genes in the receptor-PI3K pathway, and loss of function alterations in PTEN, occur frequently in cancer cells, with the result that PI3K signaling is exaggerated and cells lose growth control and exhibit enhanced survival (decreased apoptosis). Rapamycins & its congeners exert anti-tumour action from their binding to FKBP12 and inhibition of mTOR and thus inhibit cell-cycle progression, angiogenesis, and promote apoptosis.
- #30 This pathway is activated in human tumours by several mechanisms.. including binding of ligand to receptor tyrosine kinases or mutations in RAS, BRAF and MEK---This leads to activation of ERK which regulates gene transcription thereby promoting cell cycle progression and tumour survival. Also, this pathway has a classical negative feedback loop and in case of tumours with a mutant BRAF, the pathway output is enhanced due to impaired upstream feedback regulation. So, drugs against these new targets are currently in clinical development… PD325901 and AZD6244 target MEK. The clinical development of PD325901 was discontinued due to safety concerns of ocular & neurological toxicities. AZD6244 is currently in phase 2 trials in patients with BRAF mutant melanoma. Also, Phase 1 trial with a third MEK inhibitor ,GSK1 120212, have reported a high response rate of 40% in BRAF-mutant melanoma patients. In 2009 -2010, dramatic clinical response was observed with novel selective BRAF inhibitor PLX4032. Currently it is in phase 3 clinical trial. Also, impressive responses were observed in Phase 1 trial with BRAF mutant melanoma patients with more potent BRAF inhibitor GSK2118436
- #31 Other unapproved kinase inhiitors with a clear evidence of clinical activity include, 1. ALK: Anaplastic lymphoma kinase 2. Drugs specifically designed to target RET are not available, but 3 drugs i.e. Vandetanib, Sorafenib and Motesanib having activity against RET are under evaluation in phase 3 clinical trials in thyroid cancer patients. Of these, Vandetanib has recently reported improved progression-free survival 3. In approximately 30% of cases of AML, a flt-3 gene mutation creates abnormal FLT-3 receptor that promotes the growth and survival of the leukemic cells. Midostaurin is being evaluated in phase 3 trials in new cases of AML in combination with induction chemotherapy. AC 220 is the next generation flt-3 inhibitor with a impressive single agent activity in relapsed cases of flt mutant AML. 4. The discovery of JAK-2 mutations in polycythaemia, essential thrombocytosis and myelofibrosis provided a unifying understanding of myeloproliferative disorders and 2 compounds INCB018424 and TG101348 are in phase 3 and phase 2 studies respectively in myelofibrosis
- #32 NF- B is highly expressed in many human tumors, including MM, and may be a key factor in tumor cell survival in a hypoxic environment and during chemotherapy
- #33 Initial MAbs used were murine in origin and patients developed human antimouse antibody responses against the therapeutic agents. Thereafter using genetic engineering technologies, chimeric, humanized and fully human Mab’s are developed.
- #34 Therapeutic monoclonal antibodies are typically of the IgG class containing two heavy and two light chains. Initial MAbs used were murine in origin and patients developed human antimouse antibody responses against the therapeutic agents. Thereafter Advance in antibody therapeutics began in the early 1980s when using genetic engineering technologies, chimeric, humanized and fully human Mab’s are developed. Accordingly these are referred to with the suffix.. respectively
- #35 Currently , the U.S. FDA has approved 16 antibodies for the treatment of cancer and many more are under evaluation in late-stage clinical trials. Approved in 1997, rituximab is arguably the most commercially successful anticancer drug. Targeting the CD20 surface receptor common to many B cell non-Hodgkin lymphoma subtypes, rituximab is a chimeric monoclonal IgG1 antibody that induces apoptosis, antibody dependent cell cytotoxicity, and complement mediated cytotoxicity. Thereafter, Trastuzumab was approved.. The approval of gemtuzumab marked the first introduction of a plant toxin conjugated antibody. The drug received accelerated approval for patients with AML but later was withdrawn from market as drug failed to show clinical benefit in patients enrolled in trials and there were concerns regarding serious liver condition seen in post marketing surveillance Alemtuzumab, which targets CD52 was originally approved for treatment of patients with CLL ..but the company voluntarily withdrew the drug from the markets in 2012 to prevent off label use to treat multiple sclerosis and to prepare for a relaunch the drug with a different dosage and at a higher price ..which then received approval in 2014. In 2002 Ibritumomab tiuxetan became the first radioconjugated therapeutic antibody approved by the FDA in patients with NHL. Therafter, anti-CD20 murine monoclonal antibody, I131 radiolabeled-Tositumomab was approved in 2003 for the treatment of non-Hodgkin lymphoma. But, recently in 2014 drug was withdrawn due to the decline in usage !!
- #36 Then Cetuximab, Bevacizumab and Panitumumab were approved for treatment of colorectal cancer Then in 2009, a fully human anti-CD20 antibody Ofatumumab was approved for treatment of patients with CLL. Additional humanized anti-CD20 antibodies (veltuzumab and ocrelizumab) are under development. Cytotoxic T-lymphocytes can recognize and destroy cancer cells. However, there is a inhibitory mechanism that interrupts this destruction. Ipilimumab turns off this inhibitory mechanism by targeting and allows t-lymphocytes to continue to destroy the cancer cells. This human antibody was approved for patients with Metastatic melanoma. In 2011, another Immunoconjugate antibody, Brentuximab vedotin was approved for Hodgkin’s lymphoma. This is the most advanced and promising anti-CD30 construct so far, consisting of antibody and synthetic antimitotic agent.
- #37 Recently, in 2012... Pertuzumab, humanized IgG1 antibody against HER2 & Immunoconjugate antibody Adotrastuzumab received approval for Breast cancer. Obinutuzumab, a second generation Glycoengineered anti-CD 20 antibody, is approved for CLL recently in 2014. Glycoengineering is the term used to refer to manipulation of sugar molecules to improve the binding of monoclonal antibodies with immune effector cells
- #38 Coming to Mab’s which are in review … In 2014, USFDA approved Ramucirumab for gastric cancer, Pembrolizumab for Melanoma, Binatumumab for ALL and Nivolumab for melanoma. The approval of these in the European countries in pending . Blinatumomab enables a patient's T cells to recognize malignant B cells. A molecule of the drug combines two binding sites: a CD3site for T cells and a CD19 site for the target B cells and direct the human immune system to act against tumor cells. A human IgG1 antibody against EGFR, Necitumumab is in review for patients with NSCLC PD1: Programmed cell death protein 1 OR CD279
- #39 The shift from cytotoxic chemotherapy to targeted signal transduction therapy necessitates a shift in preclinical drug assessment strategies. Target validation is a critical step toward verifying a proposed mechanism of action. i.e. The drug should be tested on appropriate preclinical models in which the desired target is known to be expressed and to be important for cell/tumor survival. When designing targeted therapy, we have a specific molecular target in mind. Such projects often begin with an in vitro screen for inhibitors of that target. This will employ a cancer cell line or a genetically engineered cell line in which the target is known to be strongly activated because of either mutation or overexpression (or both) and the Lead Compound is then tested and inhibition of the target is confirmed by biochemical studies. Good in vitro models would simplify screening for cancer drugs, but, these models does not consider the role of the surrounding stromal tissue, interstitial space, blood vessels, or the immune system in tumor development. The, coming to In-vivo models.. xenograft models in immunocompromised mice are useful for preliminary pharmacological characterization. xenografts are often subcutaneous, in which case growth of a solid tumor can be easily assessed. Injecting these types of xenografts does not require any particular surgical skills. When it is important to imitate the natural environment of the tumor, such as when studying angiogenic factors, an orthotopic (i.e., to the same tissue) xenograft may be preferred. Orthotopic grafts are better models for metastatic cancer. Transgenic Models are expensive and difficult to establish but have an advantage that they can be generated in immunocompetent mice
- #40 Both hematopoietic and solid tumors include a population of self‐renewing “cancer stem cells”. Thus, even if the bulk of a tumor is eradicated, the cancer stem cells may be capable of regenerating the tumor. In vitro studies show that CML stem cells are more sensitive to interferon whereas the differentiated cells are more sensitive to Imatinib. The combination is effectively used. Erlotinib and Bevacizumab: In a clinical trial in 59 patients with metastatic RCC, tumor load was reduced by at least 50% in 21% of patients, and the disease stabilized in a further 66%. At 18 months, 60%of patients were still alive. Targeted inhibition can sensitize cancers to chemotherapy and radiotherapy such that doses can be reduced and toxic side effects minimized. About a quarter of breast cancers overexpress ErbB2. These tumors are resistant to hormone therapy and, until recently, carried a poorer prognosis. Inhibition of ErbB2 by small molecules or by the monoclonal antibody trastuzumab is synergistic with certain forms of chemotherapy and shown to improve prognosis. Also, treatment by chemotherapy plus Herceptin was twice as effective in preventing the recurrence. Furthermore, combining therapies is the most effective method to reduce the emergence of resistance
- #41 We definitely will be hearing much more about targeted therapies for cancer in the future
- #42 Targeted therapy in oncology has been a major stimulus for the evolving field of pharmacogenomics. “Personalized treatment” using genomic or proteomic techniques to determine which are the most susceptible molecular targets in a specific patient, is still a futuristic idea, but ..no longer a wild science fiction fantasy. It would be possible to predict the likelihood that a patient will respond to a specific chemotherapy regimen and to predict the risk of toxic side effects During the next several years, the field of oncology drug development will see numerous products pass through the approval process and enter the market accompanied by diagnostic tests designed to “personalize” their use, dosage, route of administration, and length of treatment for each patient, one at a time. Only time will tell whether this new approach to anticancer pharmaceuticals will yield breakthrough results, reducing morbidity and mortality and improving outcomes for all who will be afflicted with the disease