Oncology Lecture 1.pdf

Eight steps for a cell to become a cancer cell 1. Genetic instability – loss of tumor suppressors Guardians of the genome: cells normally grow in G1 phase. Guardian genes such as P16, p21, RB1 prevent cells from moving on to S phase if there is a mutation det...

Eight steps for a cell to become a cancer cell 1. Genetic instability – loss of tumor suppressors Guardians of the genome: cells normally grow in G1 phase. Guardian genes such as P16, p21, RB1 prevent cells from moving on to S phase if there is a mutation detected. Guardian genes will trigger repair mechanisms if a mutation is found. 2. Loss of polarity – loss of cell junctions Mammary epithelial cells begin to spread within cell ducts due to lack of cell junctions. This is known as hyperplasia. A normal cell has symmetry. 3. Loss of proliferative control by adjacent cells– adhesion molecule loss 4. Exit from G0, entry into cell cycle – receptors and oncogene mutations are generated. Breast cells only divide unless indicated by hormones or external factors. Breast cells normally sit at G0. Eight steps for a cell to become a cancer cell 5. Decreased ability to undergo apoptosis. 6. Loss of senescence, telomerase hTERT re- expression Normal cells divide a finite amount of times. Cell senescence is a state in which a cell permanently stops dividing but remains metabolically active; cells lose the ability to divide. Telomeres at the end of the chromosomes are used up after each cell division, cells are unable to continue replicating they are simply senescent. 7. Acquisition of invasive phenotype - key to metastasis. MMPs, (BM-collagen IV, laminin, ECM-collagen I, fibronectin. migration - external stimuli by growth factors & integrins, RhoGTPases. 8. Acquisition of angiogenic phenotype, export of angiogenic factors FGF2, VEGF Tumor Suppressors Tumor suppressor genes may be mutated, allowing for uncontrolled cell proliferation. Susceptibility genes Susceptibility genes: genetic alteration that increases an individual's susceptibility or predisposition to a certain disease or disorder. Steps to carcinogensis Cancer stem cells: Cells in in a tumor descend from a common ancestral cell that at one point--usually decades before a tumor becomes palpable--initiated a program of inappropriate reproduction. Further, the malignant transformation of a cell comes about through the accumulation of mutations in specific classes of the genes within it.These genes provide the key to understanding the processes at the root of human cancer. Hereditary Breast Cancer Cannot screen for most hereditary breast cancers Incidence goes up with early breast cancer in first degree relatives - up to 25% incidence BRCA1 and BRCA2 account for only 5% of breast cancers - 95% lifetime probability in positive patients. Screening for BRCA1 is only practical in patients with relatives positive for BRCA  Breast cancer prevention trial demonstrating a 49% reduction in breast cancer incidence in high risk women taking tamoxifen over placebo. Tamoxifen efficiently decreased breast cancer incidence in at risk women. Loss of Symmetry and polarity Normal ducts have nuclei lined up around the ducts. Cells are sitting at basement membrane and lined up shoulder to shoulder. In benign hyperplasia cells begin to grow uncontrollably into ducts. Loss of adhesion molecules allows cell membrane basement to be disturbed. Tight junctions to maintain cells shoulder to shoulder are no longer present. Loss of Proliferative Control Loss of contact inhibition Lose the ability to undergo apoptosis Exit from G0 phase, enter cell cycle. Atypical cells grow into ducts in combination with normal cells. Oncogenes, targets for gene therapy Oncogenes are turned on. Oncogenes induce RAS pathway and allow cell to enter S phase allowing cell proliferation. Cancer development Apoptosis is evaded because DNA repair genes are inactivated. Genetic Progression and the Waiting time to Cancer The adenoma grows from a population of 106 to 109 cells which accumulate mutations that drive phenotypic changes seen in cancer cells. Blue circles symbolize adenoma cells prior to accumulating the additional mutations that are the subject of modeling, Green circles are cells that have acquired additional mutations, but an insufficient number of mutations for malignancy. Red circles indicates cells with the number of mutations required for the cancer phenotype. Steps to carcinogenesis- Dead ends Results in “lead time bias” Lead time bias is a flaw of many screening trials Lead time is the length of time between the detection of a disease(usually based on new, experimental criteria) and its usual clinical presentation and diagnosis (based on traditional criteria). Lead time bias is the bias that occurs when two tests for a disease are compared, and one test (the new, experimental one) diagnoses the disease earlier, but there is no effect on the outcome of the disease--it may appear that the test prolonged survival, when in fact it only resulted in earlier diagnosis when compared to traditional methods. It is an important factor when evaluating the effectiveness of a specific test Telomerase Human telomeres consist of repeats of the sequence TTAGGG/CCCTAA at chromosome ends; these repeats are synthesized by the ribonucleoprotein enzyme telomerase hTERT Transfection of hTERT into differentiated somatic cells can induce immortalization and prevent senescence. Embryos have hTERT that assist telomerase expansion needed for cell differentiation. Normal cells undergo senescence as a response to telomere shortening after repeated divisions. However, many cancer cells activate telomerase or use alternative mechanisms to maintain telomere length, allowing them to bypass senescence. Senescence Following extensive passage (replication) in culture, oncogene activation or exposure to oxidative damage, primary cultures of mammalian cells will enter into irreversible growth arrest and display the hallmarks of the senescent cell. A number of regulatory proteins transduce senescence-inducing signals or mediate cell entry into senescence. These proteins include the p16INK4A tumor suppressor and p19ARF, which binds to and sequesters MDM2, inhibiting the MDM2-dependent degradation of p53 Loss of senescence in cancer cells refers to the ability of these cells to evade the normal processes that lead to cell cycle arrest and permanent growth cessation. Acquisition of Invasive Phenotype- key to metastasis Cancer cell will need to be motile to progress. Matrix metalloproteinases (MMPs): help degrade the extra cellular matrix. MMPs are secreted by both tumor and stromal cells. Degradation of the extracellular matrix helps metastasis and angiogenic processes. Cell Migration Normal cells do not migrate. Cancer cells are motile. 4 steps in cancer cell motility 1. Extension of lamellar pod from cell body and formation of a cohesion complex. 2. Attachment 3. Stress fiber formation that polymerize from the cohesion complex to the back of the cell. 4. The cohesion complex at the rear of the cell adheres, moving the cell. Metastasis Tumor travels to selection of secondary site Tumor invades the secondary site Tumor survival at secondary site makes a hostile micro environment Re-expression of an appropriate adhesion molecule. Acquisition of angiogenic phenotype, export of angiogenic factors FGF2, VEGF Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process in cancer progression. Tumors require a sufficient blood supply to grow beyond a certain size and to metastasize effectively. Mechanisms of angiogenesis include: A cancer benefiting micro environment Proangiogenic factors such as Vascular Endothelial growth factor (VEGF) promote blood vessel growth. Vascular count correlates with poor survival rate. Dormancy Cancer cells travel to far way organs and sleep. Cancer stem cells are dormant. dormancy – rates high mechanisms – mostly unknown most never recur – die, remain dormant, recur recurrence – adjuvant chemotherapy chemoresistance – adjuvant trials Most cancers metastasize through lymph nodes. The frequency of cytoskeleton positive cells in the bone marrow by chemotherapy Adjuvant chemotherapy is given to reduce chances of cancer returning, but micrometastasis of bone marrow was still present. Immune system targeted treatment Active anti immune mechanisms PD-L1 on tumor cells pre vent antigen presenting cells from having T cells bind to kill the cancer cell. PD-L1 inhibits T cell function. New cancer treatment inhibits the PD-L1 and allows T cell function. Principles of Chemotherapy Life cycle of human cancers relatingclinical events to population doublings There are a billion cells in a cubic centimeter. It takes a billion cells to see a tumor on an X-ray and be considered suspicious. A cancer cell divides: 2, 4, 8, 16, 32, 64, 128, 256, 512, 1024 are 10 division, each doubling meaning 210 is equal to 103 (1000). Patient will be unaware of cancer until it reaches 1010 divisions Four ways of giving chemotherapy 1. Induction treatment for advanced cancer – 1 degree or salvage, no alternatives Treating patient for advanced cancer. No alternatives available for patient, this will only maintain or shrink tumor with minimal.side effects. 2. Adjunct to local methods of treatment -adjuvant chemotherapy Given to decrease chances of cancer coming back. 3. Primary treatment for localized cancer -neoadjuvant chemotherapy Patients treated with chemotherapy to observe whether tumor is responsive to treatment and surgical prognosis. 4. Direct instillation into sanctuaries of specific regions affected by cancer Direct treatment to specific sites. 1. Induction Chemotherapy Induction chemo given when no alternative therapy exists - inoperable or metastatic Often use combinations of drugs with different mechanisms of action Define response as: complete, partial, stable disease or progression Complete response: prerequisite for cure - rare -lymphoma, leukemia, germ cell cancer Stable disease may prolong survival - concept of cancer as a chronic disease 2. Adjuvant Chemotherapy Tumor volume is at minimum or unmeasurable Treatment of micrometastatic or invisible disease Increase cure rate over that of surgery alone - eg.breast cancer Major endpoint: relapse-free survival. 3. Primary Chemotherapy (neoadjuvant) Meant to shrink tumor prior to surgery – neoadjuvant Presenting tumor is a biologic marker of response Largest tumor mass - least favorable kinetics for response to chemotherapy - slowest dividing Assume metastases have more favorable response kinetics Poor response quickly directs medication to alternate method Able to categorize prognosis by degree of response Removal of residual tumor and analysis of viability directs prognosis, eg. testicular cancer Treat to CR + 2 more cycles defines a fraction 4. Special Uses of Chemotherapy: direct installation into sanctuaries of specific regions affected by cancer Rationale: highest concentration of drug against target tumor, spare tissue, systemic effects Targeted sites: spinal fluid - by LP or Omaya reservoir -leukemia, lymphoma – therapeutic pleural, pericardial space to control effusions –palliative carotid artery - head and neck cancers, brain tumors intraperitoneal - ovarian, gastric liposomal drugs - 3 day intravascular half life Sites of Action of cytotoxic agents Cytotoxic agents targeting specific phases of the cell cycle Antimetabolites work in S phase Antibodies work in G1 and S phase Alkylating agents can kill stem cells because they work in all phases of the cell cycle. Mitosis inhibitors work in M phase. Sites of Action of cytotoxic agents Cellular level 1. DNA synthesis Targeted by antimetabolites DNA it self is targeted by alkylating agents 2. DNA transcription or DNA duplication Intercalating agents target both transcription and duplication 3. DNA duplication Is followed by Mitosis Spindle poisons target mitosis. Goldie-Coleman Hypothesis Tumor cells acquire spontaneous mutations that result in specific drug resistance between 103-106 cell stage. Detectable tumors are at least 10 9 cells Tumors at diagnosis have drug resistant clones- number depends on individual mutation rate. Combination Chemotherapy Single drugs do not cure cancer – need combinations of drugs for durable responses. Combinations developed based on biochemical actions – ineffective. Combine effective drugs from different classes of drugs that have demonstrated efficacy individually. Combination Chemotherapy Combination chemotherapy accomplishes 3 important objectives: 1. provides maximal cell kill within range of toxicity tolerated for each drug 2. provides a broader range of coverage of resistant cell lines in a heterogeneous tumor population 3. prevents or slows development of new resistant clones Principles for selecting drugs for most effective combination Select only drugs known to be partially effective when used alone - ones producing some fraction of CR preferable When several drugs in a class available, select ones whose toxicities do not overlap with toxicities of other drugs in combination - broadens range of side effects but limits lethal side effects to same organ – maximize dose intensity Principles for selecting drugs for most effective combination Use drugs in optimal dose and schedule give combinations at constant intervals Extending time between treatments allows regrowth of tumor– inter- treatment interval should be shortest possible for recovery of most sensitive tissue usually bone marrow– omission of a drug from combination may allow growth of clone sensitive to that drug alone but resistant to all other drugs arbitrary reduction of dose of an effective drug may reduce dose below threshold of effectiveness and lose chance of cure Complications of Chemotherapy Bone marrow suppression Storage compartment - able to supply mature cells to circulation for 8-10 days Nadir blood counts 10-14 days after chemo, recover by 21 days - rationale for q 3 week chemo Colony stimulating factors shorten recovery by a week Prior chemo, RT, shorten time to neutropenia and thrombocytopenia, effects of chemo more severe Nadir sepsis - abx, isolation, G/GM-CSF, RBC tx- positive blood cx - 2 week antibiotic course Complications of chemotherapy Pulmonary toxicity Drugs reported to induce toxicity: alkylating agents: busulfan, cytoxan,chlorambucil, melphalan nitrosoureas: carmustine (BCNU), lomustine(CCNU) antibiotics: Bleomycin - most common, mitomycin-C antimetabolites: methotrexate, azathioprine,mercaptopurine, Ara-C– miscellaneous: decarbazine, vinblastine Complications of chemotherapy Pulmonary toxicity Mechanisms: trigger formation of superoxide radicals, H2O2, OH radicals immune activation - prostaglandins, thymocyteactivation (mtx), PMN alveolitis (Bleo), eosinophils(procabazine, bleo, mtx) collagen deposition, fibrosis (bleo, cytoxan) inactivation of antiprotease system Complications of chemotherapy Pulmonary toxicity Predisposing factors: age >60 prior RT to lungs simultaneous O2 >35% decreased creatinine clearance (drug retained) Signs and symptoms develop over weeks to months dyspnea, “velcro” rales dry cough - not hemoptysis decreased DLCO Complications of chemotherapy Cardiac toxicity Anthracyclines- increasing cardio toxicity with cumulative doses -lifetime threshold 550 mg/m2 mediastinal RT - additive risk factor can be acute or subacute Pathology: mitochondrial swelling, disruption of myofibrils, disruption of sarcplasmic reticulum, vacuolization cardiomyopathy, decreased systolic function, exercise response liposomal formulation - no toxicity to 1200mg/m Complications of chemotherapy Cardiac toxicity Other drugs that induce cardiac toxicity: mitoxanthrone, amsacrine - MI’s cytoxan, ifosfamide - ectopy, ST changes taxol – bradicardia vincristine, vinblastine, mitomycin-C –arrhythmias 5-FU, cis-platin - arrhythmias Complications of chemotherapy Chemical Cystitis Drugs cyclophosphamide (cytoxan), used in solid tumors, lymphomas, bone marrow transplant conditioning ifosfamide, - dose limiting toxicity Unique symptoms frequency, urgency, dysuria, nocturia, microhematuria to exanguinating hemorrhage timing soon after Rx late sequelae - fibrosis, malignancy - TCC Complications of chemotherapy Chemical Cystitis Etiology - acrolein, metabolically inactive breakdown product of cytoxan and ifosfamide Concentration of acrolein in urine, bladder damage cumulative and dose related Treatment of hemmorhagic cystitis: stopping drug, replacing with azathioprin hydration, diuretics, repletion of K+ bladder irrigation Prevention - Mesna (2-mercaptoethane sulfonate) SHgroup complexes and neutralizes acrolein Complications of chemotherapy Gonadal dysfunction Testicular function in adult men susceptible to injury by many agents Primary lesion - progressive, dose related depletion of germinal epithelium lining seminiferous tubules-only Sertoli cells remain - germinal aplasia, age >45worse Clinical manifestations - reduction of volume, sperm count, infertility, increased FSH Combination chemo with alkylators worst Complications of chemotherapy Gonadal dysfunction Frequent arrest of follicular maturation or frank destruction of ova and follicles Clinical: amenorheic and have post-menopausal symptoms of estrogen deficiency, elevated LH, FSH At least half of women treated with alkylating agents develop ovarian failure - not children Adjuvant chemo for breast ca.- some amennorhea, worse with age, dose effect Anti tumor agents associated with testicular and Ovarian dysfunction Testicular germ cell depletion Ovarian dysfunction Definite: chlorambucil, cytoxan, Definite: cytoxan,busulfan, busulfan,procarbazine, nitrogenmustard, L- Nitrogenmustard, nitrosoureas phenylalaninmustard Probable: vinblastine, adria, Ara- Unlikely: Mtx, 5-FU, 6-MP C, cis-platin Unknown: adria, bleo,vinca Unlikely: Mtx., 5-FU, 6-MP, alkaloid,cis-platin,Nitrosourea, vincristin Ara-C