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  1. 1. * Cancer is a condition where cells in a specific part of the body grow and reproduce uncontrollably. The cancerous cells can invade and destroy surrounding healthy tissue, including organs. Cancer ◾The term cancer encompasses more than 200 diseases all characterized by the uncontrolled proliferation of cells. ◾When a normal cells have lost the usual control over their division, differentiation and apoptosis (programmed cell death),they become tumor cells. A tumor(Neoplasm) is the result of an abnormal proliferation of cells.
  2. 2. Cancer..... • When cancer cells break away from the main tumor and enter the bloodstream or lymphatic system. These systems carry fluids around the body. This means that the cancer cells can travel far from the original tumor and form new tumors when they settle and grow in a different part of the body. This is referred to as Metastasis. • Tumors formed from cells that have spread are called secondary tumors. The cancer may have spread to areas near the primary site, called regional metastasis, or to parts of the body that are farther away, called distant metastasis. • Cancer can spread to the skin, muscle, or other organs in the body. Cancer cells can also spread to the lining around the lungs called the pleural cavity. It can also spread to the space around the belly called the peritoneal cavity. When these cancer cells cause fluid to build up in these areas, it is called malignant pleural effusion and malignant ascites. Tumor Progression and Metastasis
  3. 3. Tumor can be either Benign or Malignant. Benign and Malignant Benign Tumors • Tumor cells remain clustered together in a single mass. • Grow slowly and have distinct borders. • Do not invade surrounding tissue. • Do not invade other parts of the body(absence of metastasis). • Benign are harmless. Malignant Tumors • Can grow quickly and have irregular borders. • Often invade surrounding tissue. • Can spread to other parts of the body through the process Metastasis.
  4. 4. Cancer Types....... • Cancers are classified according to the tissue and cell type from which they arise. ◾Carcinomas,◾ Sarcomas, ◾ Haematopoietic Cancer (Leukemia, Myeloma, Lymphoma).
  5. 5. 1. CARCINOMA • Carcinomas are cancers arising from epithelial cells. • Start in skin or the tissue that line other organs. • Epithelial tissue are the most likely to be exposed to the various forms of Physical and Chemical damage that favor the development of cancer. • Carcinoma fall into two categories- a) Squamous cell carcinoma (protective cell layer epithelia. b)Adenocarcinoma(secretory epithelia). • Most common in Humans. Carcinoma Cancer, Skin
  6. 6. 2. SARCOMA • Cancer of Mesenchymal (Embryonic connective tissue) origin. • Cancer of connective tissue such as bones, muscles, cartilages and blood vessels. • There are 50 different types of sarcoma but broadly they can be groups into soft tissue sarcoma and bone sarcoma or Osteosarcoma. Sarcoma sites...
  7. 7. 3. HAEMATOPOIETIC CANCERS • Cancer that begins in blood-forming tissue, such as the bone marrow, or in the cells of the immune system. • Examples of Haematopoietic cancer are leukemia, lymphoma, and multiple myeloma. Also called blood cancer.
  8. 8. LEUKEMIA • It is a cancer of bone marrow,which make the blood cells. • It is a cancer of blood cells caused by rise of White Blood Cells in the body. • Leukemia happens when body makes more WBC than it needs. • Two main types of WBC in our body: Lymphoid and Myeloid, Leukemia can happen in either type. • Leukemia cells can't fight infection,the way normal WBC do & because of there large number, they start to affect the major organ work. Eventually there are not enough RBC to supply O2, enough platelets to clot the blood or no enough WBC to fight infection.
  9. 9. MYELOMA Cancer of the plasma cells is Myeloma.
  10. 10. LYMPHOMA • Cancers of the lymphatic organs, especially the lymph the lymph nodes. • Also spleen, thymus gland and bone marrow. • The main types of lymphoma are Hodgkin's lymphoma and non- Hodgkin's lymphoma. Lymphoma, Translational perspective
  11. 11. Clonal Evolution • A tumor developes through repeated round of Genetic changes and proliferation. • Development of cancer requires a gradual accumulation of genetic and epigenetic changes in a number of different genes. • These changes enhance cell proliferation. • Initiation involves genetic changes. Change in the gene affect the processes associated with cellular proliferation, survival and differentiation. Promotion is associated with increased proliferation of the initiated cell. It lengthy and reversible process where preneoplastic cell accumulate. Progression is final stage of neoplastic transformation. Genetic and Epigenetic changes within cells of tumor population. Epigenetic changes become dominant within tumor population (clonal selection).
  12. 12. Cancer cell, Properties... • Cancer cells are immortal and can grow indefinitely. • Proliferation of cancer cells is not sensitive to density dependent inhibition. • Invasiveness refers to ability of tumor cells to invade neighbouring tissue. • Metastasis • Cancer cell also secrete growth factors that promote formation of new blood vessels (Angiogenesis). • Autocrine stimulation drives the proliferation of tumor cells continuously. • Fail to undergo apoptosis, exhibit increased life spans.
  13. 13. Molecular Basis and Genetics ◾Cellular functions are controlled by proteins, and because these proteins are encoded by DNA organized into genes, molecular studies shown that cancer is a paradigm of acquired genetic disease. Tumor Suppressor Gene Proto-oncogene Oncogene Carcinogen Point Mutation Chromosomal Translocation Benign versus Malignant
  14. 14. Proto-oncogene; Oncogene • There are trillions of living cells in the body that grow, divide, and die in an orderly fashion. This process is tightly regulated by the genes within a cell’s nucleus. These genes code for proteins that help regulate cell growth. These important genes are called proto-oncogenes. • A change or Mutation in the DNA sequence of the proto-oncogene gives rise to an oncogene, which produces a different protein and interferes with normal cell regulation. • A mutated or defective version of a proto-oncogene (oncogene) increases the production of these proteins, thereby leading to unregulated cell division, a slower rate of cell differentiation and increased inhibition of cell death. • Together, these features define cells that have become cancerous. ◾Several genetic mechanisms that cause a proto-oncogene to become an oncogene. • Point mutations, insertions or deletions that give rise to an overactive gene product. • Point mutations, insertions or deletions that lead to an increase in transcription • Gene amplification leading to additional copies of a proto-oncogene • Chromosomal translocation that causes a proto-oncogene to move to a different chromosomal site associated with increased expression • Chromosomal translocations that cause a proto-oncogene to fuse with another gene to produce a protein that has oncogenic activity.
  15. 15. Point Mutation • When a mutation occurs in a proto-oncogene, it becomes permanently turned on (activated). • The gene will then start to make too much of the proteins that code for cell growth. Cell growth occurs uncontrollably. • This alteration may be the deletion of a base, insertion. • It can increase gene function or can interrupt gene function. Converting proto-oncogene to oncogene An oncogene is a dominantly expressed mutated gene that renders a cell advantageous towards survival. Oncogenes act in a dominant manner,gain of mutation in a single copy of the cancer critical gene can drive a cell toward cancer. RAS proto-oncogene. HER2 gene. This gene codes for a transmembrane tyrosine kinase receptor called human epidermal growth factor receptor 2
  16. 16. Chromosomal Translocation • Chromosomal translocations are favored in neighboring chromosomes or genes in spatial proximity within the nucleus. • Chromosomal translocations leading to cancer are generally via two ways, formation of oncogenic fusion protein or oncogene activation by a new promoter or enhancer. • Burkittt's Lymphoma (Translocation induced overexpression of Proto-oncogene). • MYC Containing segment of Chromosome-8 translocate to Chromosome-14. • Translocation places MYC gene close to Ig heavy chain gene. • Translocated MYC gene regulated by Ig gene enhancer and cell to become cancerous. • MYC proto-oncogene protein act as a Transcription factor. • MYC family consists 3 related human gene; c-myc(MYC), l- myc(MYCL), n-myc(MYCN). Burkittt's Lymphoma Translocation
  17. 17. Translocation cont..... • Chronic myelogenous leukemia(chronic myeloid leukemia or chronic granulocytic leukemia) occurs when something goes awry in the genes of your bone marrow cells. • People with chronic myelogenous leukemia, the chromosomes in the blood cells swap sections with each other. • A section of chromosome 9 switches places with a section of chromosome 22, creating an extra-short chromosome 22 and an extra-long chromosome 9. • Abnormal Philadelphia chromosome (ph1) result of balanced reciprocal 9;22 Translocation. • Genes from chromosome 9 combine with genes from chromosome 22 to create a new gene called BCR-ABL. • The BCR-ABL gene contains instructions that tell the abnormal blood cell to produce too much of a protein called tyrosine kinase. • Tyrosine kinase promotes cancer by allowing certain blood cells to grow out of control. Generation of BCR-ABL gene by Translocation
  18. 18. Oncogenic Chromosomal Translocation • Chronic myelogenous Leukemia ➡️ Chromosomal Translocation (9;22) • Acute myelogenous Leukemia ➡️ Translocation (8;21) • Retinoblastom a ➡️ Deletion (13q)
  19. 19. Activation of MYC oncogene by Insertion • Expression of MYC gene is elevated after the insertion of a non defective retrovirus in the vicinity of the gene. • ALV(Avian leukosis virus) retrovirus doesn't carry any viral oncogenes,yet able to transform B cell into lymphomas. • ALV integrate within MYC proto-oncogene,which contains 3 exons. • Exon-1 has an unknown function; Exon-2 and 3 encode with MYC protein. • Insertion of ALV between exon 1 & 2 allow the provirus promoter to increase transcription of exons 2 & 3, resulting increased synthesis of MYC protein.
  20. 20. Tumor Suppressor Gene • Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death). • When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer. • An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated (turned off). • Tumor suppressor genes are also known as antioncogenes or loss-of-function genes. • Most tumor suppressor gene mutations are acquired, not inherited. • Example of some tumor suppressor genes:- • p53 gene: The p53 gene (TP53) creates protein p53 which regulates gene repair in cells. Mutations in this gene are implicated in around 50 percent of cancers. Inherited mutations in the p53 gene are much less common than acquired mutations and result in the hereditary condition known as Li Fraumeni syndrome. The p53 codes for proteins that tell cells to die if they are damaged beyond repair, a process referred to as apoptosis. • BRCA1/BRCA2 genes: These genes are responsible for around 5 percent to 10 percent of breast cancers. • APC gene: These genes are associated with an increased risk of colon cancer in people with familial adenomatous polyposis. • PTEN gene: The PTEN gene is one of the non-BRCA genes that can increase the risk of a woman developing breast cancer (up to an 85 percent lifetime risk). It is associated with both PTEN hamartoma tumor syndrome and Cowden syndrome. • RB1:- cell cycle check point. • hMLH1 gene :- DNA mismatch repair. • NF1 gene:- GTPase
  21. 21. Tumor Suppressor Gene • Genes that regulate or inhibit cell cycle progression.(RB1) • Genes that encode receptors or developmental signals that inhibit cell proliferation (Hedgehog receptor). • Genes encoding checkpoint-control proteins that arrest cell cycle if DNA is damaged (TP53). • Genes that promote Apoptosis. • Genes that encode enzymes that participate in DNA repair. • Mutations in Tumor Suppressor Gene generally act in a recessive manner. • Function of both alleles of the cancer critical gene drive a cell toward cancer. • Mutation of some tumor suppressor genes can have an effect even when only one of the two gene copies is damaged.
  22. 22. TP53 Gene • The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53). • This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way. • When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or UVrays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct . • If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors. • It is also known as the "guardian of the genome." • Mutation in TP53 Gene are associated with more than 50% human cancer. • Loss of P53 abolishes the DNA damage checkpoint. • Cells with functional p53 become arrested in G1 when exposed to DNA damaging irradiation, whereas cells lacking functional p53 do not.This permits the cells to repair the DNA damage prior to stages of it fixation and propagation, which leads tumor formation.
  23. 23. p53 Mutation • In most cases, the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a hallmark of cancer cells. Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional oncogenic functions that endow cells with growth and survival advantages. • Interestingly, mutations in the p53 gene were shown to occur at different phases of the multistep process of malignant transformation, thus contributing differentially to tumor initiation, promotion, aggressiveness, and metastasis. • The importance of p53 as a cardinal player in protecting against cancer development is further emphasized by Li-Fraumeni syndrome (LFS), a rare type of cancer predisposition syndrome associated with germline TP53 mutations. • The TP53 gene in human tumors is often found to undergo missense mutations, in which a single nucleotide is substituted by another. • APC gene mutation and beta-catenin accumulation preceded the loss of chromosome 17p,. • The aberrant accumulation of beta-catenin in tumors results from p53 inactivation. • A mutation in TP53 at an early stage of cancer progression can occur due to exposure to a carcinogen. • Aflatoxin B1 induces a G:C to T:A transversion in codon 249 of the TP53.Aflatoxin B1 was also found to be enzymatically activated in human hepatocytes and to bind to the third base of codon 249.The expression of the 249 serine mutation was further shown to inhibit p53-dependent apoptosis and transcription and enhance liver cell growth in vitro.This mutation was also found in nontumorous liver in correlation with aflatoxin B1 intake, highlighting the notion that this mutation can occur early in the process of malignant transformation. • Loss of function mutations in other tumor suppressor gene are recessive because the encoded protein function as monomers and Mutation of a single allele has little functional consequence effect.
  24. 24. p53 Mutation.....cont. Mutant p53 as a guardian of the cancer cell. Mutant p53 in Cancer
  25. 25. RB Gene and it's genetic mechanism • RB Gene is missing in several common types of sporadic cancer (lung,breast, bladder). • RB Gene encodes the RB protein, which is universal regulator of the cell cycle. • Mutations in the RB1 gene are responsible for most cases of retinoblastoma. • The RB/E2F pathway regulates apoptosis, G1-S phase transition and RB inhibition of apoptosis is an important mechanism of tumor suppression whereby cells deficient for RB function can be eliminated by apoptosis. • One manner through which RB can inhibit apoptosis is through its binding to RNA processing factors. • Cyclin D1-CDK4 complex phosphorylates RB, leading to dissociation from the RB-E2F complex, which frees E2F for activation of cyclin D1 and S phase gene transcription. • Positive feedback loop among RB, E2F, and cyclin D1 allows for cell cycle progression through G1/S and S phase. • Deregulation of RB pathways occur in most cancer and is mediated either by loss of function mutation of negative players including RB and CDK inhibitors (CKIs,p15,p21 etc ) or by amplification or overexpression of cyclin D1.
  26. 26. RB Gene... Mechanism of RB inactivation The Genetic mechanisms that cause Retinoblastoma • All cells in the lack one of the normal 2 functional copy of Rb tumor suppressor gene, tumor occur where the remaining copy is lost or inactivated by mutation or epigenetic silencing. • In nonhereditary form all cells initially contain 2 functional copies of the gene.And tumor because both copy are lost or inactivated.
  27. 27. BRCA1 & BRCA2 • BReast-CAncer susceptibility gene1 and 2 are tumor suppressor gene. • The two genes most responsible for breast cancer and ovarian cancer. • Mutations to the BRCA1 and BRCA2 genes are inherited, either from a person's mother or father (or both), and these are linked to an increased risk for cancer. • Maintain genome stability through repair of DNA double strand breaks by homologous recombination, cell growth regulation and control of cell division. • Individuals carrying germline pathogenic mutation in BRCA1 or BRCA2 are at highly risk of breast or ovarian cancer. BRCA Mutation
  28. 28. • The number of mutations required for neoplastic transformation may vary, all tumors are reliant on two critical mechanisms for their development; the activation of oncogenes that promote proliferation and survival of cancer cells, as well as the inactivation of tumor suppressor genes that normally repress development and growth of tumors. • Oncogenes can be activated via multiple mechanisms, including chromosomal translocations, deletions or insertions, as well as point mutations. • Tumor suppressor genes can be inactivated through multiple mechanisms, including large-scale chromosomal alterations or point mutations. • Anti-apoptopic genes such as BCL-2 behave as Proto-oncogenes because overproduction of their encoded proteins prevent normal apoptosis. • Apoptopic genes whose protein products stimulate apoptosis behave as tumor suppressors. Points to Remember
  29. 29. CARCINOGEN • A carcinogen is a specific chemical or physical agent that has the ability to cause cancer in individuals exposed to that agent. • Initiate or promote tumor formation. • Three classes of Carcinogen a) Physical (UV-ray, gamma-ray) b) Chemical (benzopyrene, benzene) c) Biological (oncovirus) • There are two types of chemical carcinogen- 1) Direct acting (act directly without any metabolic activation) and 2) Indirect acting(require metabolic activation). • Chemical carcinogens are mostly Tumor Initiators,cause cancer by inducing Mutation. • Some are Tumor Promoter. • Phorbol esters stimulate cell proliferation by activating protein kinase C. • Aflatoxin (a myotoxin)- Indirect acting Carcinogen. • Activated into aflatoxin- 2,3, epoxide by the action of intracellular enzymes which is associated with mutation of the p53 gene. • Aflatoxin is produced by the fungus Aspergillus flavus and Aspergillus parasitics. • Aflatoxin consists of a difurofuran ring system fused to a substituted coumarin moiety with a methoxy group attach at the corresponding benzene ring. • After chemical modification by liver enzymes aflatoxin becomes linked to G- residues in DNA and induces G-T transversion. • Other chemical carcinogen associated with human cancer is- • Benzene (Leukemia), Arsenic (lung and skin), Cadmium (prostate), Radon (lung), Asbestos (lung,GI tract) Vinyl Chloride (Angiosercoma,Liver).
  30. 30. Chemical Carcinogen and their effect on genome;
  31. 31. Oncovirus Onco= Relating to tumor Virus= Infectious agent • Oncovirus- a virus that can cause cancer. This Viruses infect healthy cells and transform them to infected one, creating tumor producing potential in the cells. • This virus can contain DNA or RNA or both as their genetic material and basically responsible for tumor or cancer cause. • The vast majority of human and animal virus do not cause cancer most probably because of longstanding co-evolution of host and virus. • Most of the cancer that occurs because of these viruses can be prevented if vaccination is taken on proper time. • Diagnosis can be done through simple blood tests and can be treated with non-toxic antiviral compound also. • It is difficult to detect the virus until it infect the host.
  32. 32. Types of Oncovirus DNA Oncogenic Virus RNA Oncogenic Virus • Oncogenic DNA viruses include EBV, hepatitis B virus (HBV), human papillomavirus (HPV), human herpesvirus-8 (HHV-8), and Merkel cell polyomavirus (MCPyV). Oncogenic RNA viruses include, hepatitis C virus (HCV) and human T-cell lymphotropic virus-1 (HTLV-1). • The Epstein-Barr virus has been linked to Burkitt’s lymphoma. This virus infects B cells of the immune system and epithelial cells. • The hepatitis B virus has been linked to liver cancer in people with chronic infections. • Human papilloma viruses have been linked to cervical cancer. They also cause warts and benign papillomas. This virus uses 2 viral proteins, E6 and E7 to sequester the host cells p53 and Rb respectively. • E1A and E1B proteins of adenovirus inactivate the RB and p53 tumor suppressor protein with E1A binding to RB and E1B binding to p53. • Human herpes virus-8 has been linked to the development of Kaposi sarcoma. • DNA tumor viruses have two life-styles. In permissive cells, all parts of the viral genome are expressed. This leads to viral replication, cell lysis and cell death. In cells that are non-permissive for replication, viral DNA is usually, but not always, integrated into the cell chromosomes at random sites. Only part of the viral genome is expressed. DNA Contain Oncovirus
  33. 33. • Viral oncogene first reported in Rous Sarcoma virus by Peyton Rous, which transforms chicken embryo fibroblasts in culture and induces Sarcoma. • The first oncogene found in Rous Sarcoma virus, designated as src oncogene. • Oncogenic RNA viruses include, hepatitis C virus (HCV) and human T-cell lymphotropic virus-1 (HTLV-1), HTLV-2(Hairy cell Leukemia). • Viral cancers do not arise acutely after infection, but instead develop 15–40 years later. • Hepatitis C virus is an enveloped RNA virus capable of causing acute and chronic hepatitis in humans by infecting liver cells. It is estimated 3% of the world’s population are carriers. Chronic infection with hepatitis C virus results in cirrhosis, which in turn can lead to liver cancer. • Hepatitis viruses includes hepatitis B and hepatitis C have been linked to hepatocellular carcinoma. • Simian virus 40,SV40 (Non-Hodgkin's lymphoma). Retroviral Oncogene:- • Normal chicken cells contain genes that are closely related to retroviral src oncogene (codes for Src protein kinase) of Rous Sarcoma virus (H. Varmous & M. Bishop). • The oncogene in the virus did not represent true viral gene,but was a normal cellular gene, which the virus acquired during replication in host cell. • src related sequences also found in normal DNA of a wide range of vertebrate (including human). • The normal genes from which the retroviral oncogene originate are called proto- oncogene. • Mutations or genetic rearrangement of Proto-oncogenes by Carcinogen or viruses alter the normally regulated function of these genes. • v-viral Oncogene and c-cellular Oncogene. • Oncogene carried by Rous sarcoma is called v-src and proto-oncogene related to it in cellular genomes is called v-src. RNA Containing Oncovirus
  34. 34. V I R A L vs C E L L U L A R O N C O G E N E
  35. 35. Therapeutic Interventions Supportive care services describe a broad range of therapies designed to combat side effects and maintain well-being. Treating cancer requires focusing on more than the disease alone; it must also address the pain, fatigue, depression and other side effects that come with it. • Nutrition therapy to help prevent malnutrition and reduce side effects • Naturopathic support to use natural remedies to boost energy and reduce side effects • Oncology rehabilitation to rebuild strength and overcome some of the physical effects of treatment • Mind-body medicine to improve emotional well-being through counseling, stress management techniques and support groups • Treatment options depend on the type of cancer, its stage, if the cancer has spread and your general health. The goal of treatment is to kill as many cancerous cells while reducing damage to normal cells nearby. Advances in technology make this possible. • The three main treatments are: • Surgery: directly removing the tumor • Chemotherapy: using chemicals to kill cancer cells • Radiation therapy: using X-rays to kill cancer cells.
  36. 36. Treatment... • Cell-lethal combination with some lesion that is present in the cancer cells,but harmless to cells where this lesion is absent (synthetic lethal);it kills only in partnership with the cancer-specific mutation. • PARP Inhibitors kill cancer cells that have Defects in Brca1 or Brca2 genes. • Design of small molecules to inhibit specific Oncogenic protein. eg-Chimeric Bcr-Abl protein can inhibit by drug molecules imatinib, blocks Bcr-Abl by inhibit the activity of tyrosine kinase. • The MAP kinase (MAPK) pathway has emerged as the crucial route between membrane-bound Ras and the nucleus. The MAPK pathway encompasses a cascade of phosphorylation events involving three key kinases, namely Raf, MEK (MAP kinase kinase) and ERK (MAP kinase). This kinase cascade presents novel opportunities for the development of new cancer therapies designed to be less toxic than conventional chemotherapeutic drugs. • Furthermore, as a signal transduction-based approach to cancer treatment, inhibition of any one of these targets has the potential for translational pharmacodynamic evaluation of target suppression.
  37. 37. • The Ras-MAPK (Mitogen Activated Protein Kinase) pathway begins with growth factor binding to transmembrane Receptor Tyrosine Kinases (RTKs). • Growth factor binding initiates homodimerization and auto-phosphorylation in trans at specific tyrosines of the RTKs. • Growth factor receptor-bound protein 2 (Grb2) is then recruited to the cytosolic portion of the RTKs via a Src homology 2 (SH2) domain which binds to phosphotyrosines. Grb2 then recruits a guanine exchange factor, Son of Sevenless (SOS), via an SH3 domain and the GTPase Ras. • Ras, a protein that was originally identified as the transforming component in oncogenic viruses, is then post- translationally modified with an isoprenyl group that localizes it to the plasma membrane. • The GTPase activity of Ras is enhanced by the GTPase Activating Protein (GAP). • Ras recruits and activates the MAPK kinase kinase (MAPKKK) Raf which initiates a phosphorylation cascade from Raf to MEK (MAPKK) which finally phosphorylates ERK (MAPK, Extracellar Regulated Kinase). • Phosphorylated ERK then translocates to the nucleus where it phosphorylates transcription factors important for proliferation and differentiation. • Oncogene activation of the ERK MAPK cascade. Mutationally activated B-Raf, Ras and mutationally activated (by missense mutations in the cytoplasmic kinase domain in NSCLC or by extracellular domain truncations (e.g., VIII) in glioblastomas) and/or overexpressed EGFR causes persistent activation of the ERK MAPK cascade in human cancers. • Activated ERKs translocate to the nucleus, where they phosphorylate and regulate various transcription factors leading to changes in gene expression. • In particular, ERK-mediated transcription can result in the upregulation of EGFR ligands, such as TGFα, thus creating an autocrine feedback loop that is critical for Ras-mediated transformation and Raf-mediated gene expression changes
  38. 38. Immunotherapy • Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer. This can be done in a couple of ways: • Stimulating, or boosting, the natural defenses of your immune system so it works harder or smarter to find and attack cancer cells • Making substances in a lab that are just like immune system components and using them to help restore or improve how your immune system works to find and attack cancer cells. • Checkpoint inhibitors: These drugs basically take the ‘brakes’ off the immune system, which helps it recognize and attack cancer cells. • Chimeric antigen receptor (CAR) T-cell therapy: This therapy takes some T-cells from a patient's blood, mixes them with a special virus that makes the T-cells learn how to attach to tumor cells, and then gives the cells back to the patient so they can find, attach to, and kill the cancer. • Cytokines: This treatment uses cytokines (small proteins that carry messages between cells) to stimulate the immune cells to attack cancer. • Immunomodulators: This group of drugs generally boosts parts of the immune system to treat certain types of cancer. • Cancer vaccines: Vaccines are substances put into the body to start an immune response against certain diseases. We usually think of them as being given to healthy people to help prevent infections. But some vaccines can help prevent or treat cancer. • Monoclonal antibodies (mAbs or MoAbs): These are man-made versions of immune system proteins. mAbs can be very useful in treating cancer because they can be designed to attack a very specific part of a cancer cell. • Oncolytic viruses: This treatment uses viruses that have been modified in a lab to infect and kill certain tumor cells. • A monoclonal antibody called trastuzumab that binds to Her2 and inhibits it's functions slows the growth of breast tumors in humans that overexpress Her2,it is now an approved therapy.