OMONDI OGUDE MEDICAL ONCOLOGY

Transcription

1 OMONDI OGUDE MEDICAL ONCOLOGY

2

3 Personalized medicine (Targeted therapy) In recent years there s been a move from conventional cytotoxic therapy to more targeted therapy Mostly due to the rapid pace of progress in the fields of biotechnology, genetics, and genomics. As a result, Molecular Genetic Profiling has increasingly becoming an integral tool for clinicians to guide individualized management of many medical conditions, especially cancer

4

5 The aim of targeted therapy is to Interfere with specific targeted molecules needed for carcinogenesis and tumour growth These drugs include MAb, Immunotherapy, Radioisotope therapy and Tyrosine Kinase Inhibitors

6 Tyrosine Kinase Tyrosine Kinases are trans-membrane receptors that activate signal pathways after binding of there respective ligands Tyrosine kinases are activated by binding of Ligands (signal molecules) such as VEGF AND EGF This occurs by transfer of a phosphate group to a tyrosine residue

7 TYROSINE KINASE RECEPTORS a) INACTIVE MONOMERS b) ACTIVATED DIMERISED RECEPTORS

8 TYROSINE KINASE RECEPTOR SIGNALLING Cell growth and control occurs in response to signalling pathways which occurs via Tyrosine Kinases. At least 90 TK genes and 43 TK-like genes are present in humans, coding for TKs with important regulatory functions, include cellular proliferation, survival, differentiation, function, and motility.

9 TYROSINE KINASES TKS function like and can be thought of as light switches They function as "on" or "off" switches for the cellular signalling pathways Protein kinases can however become mutated, and become stuck in the "on" position, and cause unregulated growth of the cell, which is a necessary step for the development of cancer.

10 Endothelial Cell VEGF-B VEGF-A VEGF-C VEGF-D VEGF-R1 (Flt-1) VEGF-R2 (KDR) VEGF-R3 (Flt-4) MIGRATION PROLIFERATION MIGRATION Ras Raf MEK PI3K Akt Caspase-9 enos p38mapk ERK CELL ACTIVATION / SURVIVAL ANGIOGENESIS VASCULOGENESIS LYMPHANGIOGENESIS

11 Development of Mutations Two ways in which mutations can develop: Single mutation model (eg cml). Multiple hit model (eg colon cancer, breast cancer).

12 Driver Mutations Mutations occur in cancer cells in genes encoding for proteins critical to cell growth and survival These are known as driver mutations. Driver mutations are the mutations in the respective malignant cells that drive the neoplastic process. Driver mutations are typically not found in the germline (noncancer) cells of the host and are usually mutually exclusive (ie, a cancer is unlikely to have more than one driver mutation)

13 These mutations occur in the genome of cancer cells within genes that encode for proteins critical to cell growth and survival. Driver mutations often impart an oncogene-addicted biology to the transformed cell, which means that the cancer cell relies on the driver to receive a signal in order to survive.

14 Some of the best characterized of these biomarkers are EGFR mutations and ALK translocation as well as the Philadelphia chromosome.

15

16 Rationale for Tyrosine Kinase Inhibitors The goal is to prevent the cascade of reactions critical for tumor cell function and to inhibit its growth or survival by inhibiting the targeted driver mutations Preferentially kill malignant cells, and to a degree spare to normal cells. The added advantage is that these drugs are administered orally

17 TYROSINE KINASE INIBITORS Imatinib Mesylate, Dasatinib, and Nilotinib. eg: Lapatinib. eg: Gefitinib, Semaxinib, Vatalanib, Sunitinib, Sorafenib. eg.

18 CML CHRONIC MYELOID LEUKEMIA (CML) IS A CLONAL STEM CELL DISORDER CHARACTERIZED BY MASSIVE EXPANSION OF CELLS OF THE MYELOID LINEAGE. RESULTS FROM THE FUSION OF A TK WITH A PARTNER PROTEIN, DUE TO A BALANCED CHROMOSOMAL TRANSLOCATION 9:22.

19 MOLECULAR CONSEQUENCE OF THIS TRANSLOCATION IS THE SYNTHESIS OF THE FUSION PROTEIN BCR-ABL, A CONSTITUTIVELY ACTIVATED TYROSINE KINASE, THIS LEADS TO AUTOACTIVATION OF THE TK EVEN, IN THE ABSENCE OF LIGAND BINDING.

20 Light switch

21 First molecularly targeted protein kinase inhibitor to receive FDA approval. It targets the BCR-ABL tyrosine kinase, which is the driver mutation in chronic myelogenous leukemia (CML). BCR-ABL tyrosine kinase is present in all patients with chronic myelogenous leukemia (CML) and some patients with acute lymphoblastic leukemia (ALL)

22

23 TREATMENT OF EARLY STAGE (CHRONIC) CML WITH GLEEVEC LEADS TO AN HAEMATOLOGIC RESPONSE IN 90% OF CASES BLOOD SMEARS SHOW A PROFOUND SHIFT IN CELLULAR COMPOSITION & APPEAR MICROSCOPICALLY NORMAL PCR ANALYSIS REVEALS A LARGE DECLINE IN BCR-ABL mrna IN BLOOD CELLS. IN 50% OF CASES, THE PHILADELPHIA CHROMOSOME IS NO LONGER DETECTABLE

24 MEASURING CLINICAL RESPONSE TO GLEEVEC CYTOLOGICAL RESPONSE- LEUKEMIC CELLS WITH LARGE DARK NUCLEI ARE CONVERTED TO NORMAL GRANULOCYTES. qpcr measures Bcr-Abl mrna levels- CAN DETECT ONE CML CELL IN NORMAL BLOOD CELLS. UNTREATED PATIENT- 50% OF MAXIMUM PCR AMPLIFICATION AT CYCLE 29; AFTER GLEEVEC, SAME AMOUNT OF AMPLIFICATION IS SEEN ONLY AT CYCLE 39. REDUCTION IN BCR-ABL CELLS BY A FACTOR 2 10

25 Most Common Adverse Events (by 5 Years) Imatinib is a Safe Drug... IRIS Study: Most Frequently Reported AEs All Grade AEs Patients, % Grade 3/4 AE s Patients % Superficial Edema 60 2 Nausea 50 1 Muscle cramps 49 2 Musculoskeletal pain 47 5 Diarrhea 45 3 Rash/skin problems 40 3 Fatigue 39 2 Headache 37 <1 Abdominal pain 37 4 Joint pain 31 3 Only Serious Adverse Events (SAEs) were collected after 2005 Grade 3/4 adverse events decreased in incidence after years 1-2 IRIS 8 year update

26 Gastrointestinal Nausea, vomiting, abdominal pain Edema Periorbital edema or peripheral edema in the lower extremities Diarrhea Muscle cramps Fatigue Skin rash Cytopenias

27 Some Patients In Chronic-phase Cml And Even More Patients With Advanced-phase Disease Demonstrate Resistance To Imatinib Or Develop Resistance During Treatment. In 40% To 50% Of Cases, This Is Attributed To The Development Of Mutations These Prevent/Impair The Ability Of Imatinib To Bind To The Catalytic Cleft

28 Resistance to Imstinib resistance to treatment with tyrosine kinase inhibitors (TKIs) is divided into two categories: primary and secondary rimary resistance is when a patient fails to achieve a desired response to treatment and occurs in up to 25 percent of patients receiving imatinib as initial treatment for chronic phase CML Secondary resistance occurs when patients with an initial response I Imatinib ultimately relapse. This proportion has been estimated at 80, 50, and 15 percent at approximately two years for patients in blast crisis, accelerated phase, or chronic phase, respectively

29 Primary resistance. There are two main mechanisms that are theoretically possible Insufficient inhibition of the Bcr-Abl tyrosine kinase Decreased numbers of normal hematopoietic cells resulting in failure to recover normal blood counts. The mechanisms of secondary resistance are varied but most commonly involve reactivation of Bcr-Abl signaling and/or the activation of other signaling pathways, such as Src kinase

30 SECOND GENERATION BCR-ABL INHIBITORS THESE INCLUDE: DASATINIB, A POTENT DUAL BCR-ABL AND SRC INHIBITOR; NILOTINIB, A SELECTIVE, POTENT BCR-ABL INHIBITOR; BOSUTINIB A SRC-ABL INHIBITOR PONATINIB ONLY TKI WITH activity against T315I MUTATION NOVEL, MORE POTENT TKI S DEVELOPED THAT CAN OVERCOME NOT ONLY BCR-ABL DEPENDENT MECHANISMS OF RESISTANCE, BUT ALSO THOSE THAT ARE BCR-ABL INDEPENDENT.

31 KIT RECEPTOR INHIBITION GLEEVEC USEFUL IN TREATING GISTS IN 85% OF PATIENTS, THE KIT RECEPTOR IS MUTATED WHILE 3-5% HAVE MUTATED PDGF-Rα THE RECEPTORS FIRE CONTINUOUSLY & ARE THE PRIMARY MITOGENIC FORCES IN THE TUMOURS AS AN ADJUVANT RX FOLLOWING EXCISION OF LOCALIZED PRIMARY TUMOURS, GLEEVEC OFFERS LONG TERM SURVIVAL THAT MAY LEAD TO CURE. WITH METASTATIC DISEASE, GIST COLONIES REGRESS, BUT WITHIN A YEAR/2, TUMOUR REAPPEARS.

32 Imatinib (Gleevec ) FDA Approved Indications Chronic Myeloid Leukemia Pediatric CML Acute Lymphoblastic Leukemia Gastrointestinal Stromal Tumors Myelodysplastic/Myeloproliferative Diseases Aggressive Systemic Mastocytosis Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia Dermatofibrosarcoma Protuberans

33 MULTI TARGETED KINASE INHIBITORS MTKI Block signaling pathways at various levels The risk with blocking a single point in the pathway is that the escape pathway may develop as there is a lot overlap between signaling pathways MTKI can mitigate this by inhibiting kinases at several levels thus increasing efficacy but at the expense of specificity and increased toxicity MTKI are often referred to as Dirty Molecules

34 Bevacizumab VEGF-B VEGF-A VEGF-C VEGF-D VEGF-R1 (Flt-1) VEGF-R2 (KDR) VEGF-R3 (Flt-4) Vandetanib PTK/ZK Sunitinib MIGRATION Motesanib PROLIFERATION MIGRATION Sorafenib p38mapk Ras Raf MEK ERK PI3K Akt Caspase-9 enos CELL ACTIVATION SURVIVAL ANGIOGENESIS VASCULOGENESIS LYMPHANGIOGENESIS

35 Multitargeted TKI Toxicities Hypertension Fatigue Increased clotting events Bleeding (epistaxis, pulmonary hemorrhage, tumor associated) Headache Neurologic events Increased LFTs Pain at tumor sites Proteinuria Hypothyroidism? And Skin rash Myelosuppression Nausea/vomiting Diarrhea Others

36 Toxicity Multitargeted Agents: Trade-off Between Toxicity and Efficacy? Increasing inhibition of each kinase: unknown effect High toxicity, low efficacy Low toxicity, high efficacy Efficacy

37 Use Of TKI in other Malignancies

38 NSCL- Adenocarcinoma ROS1/ALK MUTATIONS: CRIZOTINIB CERITINIB EGFR MUTATIONS ERLOTINIB AFATINIB GEFITINIB

39

40

41

42

43 TKI in Melanoma

44

45

46 TKI in non cancerous conditions Fibrogenic growth factors have been implicated in the pathogenesis of Interstial Pulmonary Fibrosids Nintedanib Nintedanib, a receptor blocker for multiple tyrosine kinases that are responsible for fibrogenic growth factors (eg, platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor), appears to slow the rate of disease progression in IPF. In INPULSIS-1 study, the annual rate of decline in forced vital capacity (FVC) was lower in the nintedanib group than the placebo group with a difference of ml/year. The results were similar in INPULSIS-2 where the difference in FVC decline was 93.7 ml/year (95% CI ). An increase in the time to first exacerbation was noted (hazard ratio 0.38, 95% CI ). The most frequent adverse effects associated with nintedanib were diarrhea and elevation in liver function tests

47 Issues with TKI Cost Cost Cost Although efficacious in some cancers, the responses are not often durable due to rapid development of resistance

48 Pathways in Cancer

49 Are TKIs Revolutionary? YES!!! Since the advent of Imatinib, the FDA has approved the multiple other TKIs in over 20 cancers (and non cancerous conditions) A lot of theses have now been established as first line Rx and the standard of care in these condition There effective with relatively low toxicity and are generally well tolerated TKIs have changed how we view cancer and research drugs and this has spurred on other forms of treatment such as chekpoint inhibtors which are also like to change the face of Oncology in the next few years

50 Thank You