Molecular basis of cancer and brief introduction to cancer chemotherapy

1. Cancer: General Principles
10 April 2023
Dr Lakhan Kashyap
Assistant Professor
Department of Medical Oncology
Dr DY Patil Medical College and Hospital, Pune

2. • General biology
• Classification
• Etiopathogenesis
• Benign and Malignant tumor
• Invasion and metastases
• Basic principle of cancer therapy
• Chemotherapy of breast cancer and leukemia

3. Cancer
• Abnormal proliferation of cells
• Without control
• Ability to invade other tissue

4. The nature of cancer
• Cardinal features
• Growth
• Invasion
• Metastasis
• All the morphological or biochemical changes/process present in
cancer cells are also present in normal cell
• Loss of regulation
• Rate of cell division is not greater than normal cells
• Cell cycle shortens
• Higher proportion of cells undergoing division

5. Principles of carcinogenesis
• Neoplastic transformation is a progressive process involving multiple
“hits” or genetic changes.
• Alterations in DNA cause changes in one or more of the following
types of genes:
• Proto- oncogenes
• Tumor suppressor genes
• Genes regulate apoptosis
• DNA repair genes

7. Multi-hit model of Cancer
• loss-of-function mutations in the APC
tumor-suppressor gene (APC,
adenomatous polyposis coli) occur in all
polyps
• APC- and rasD mutations occur in the
benign adenoma stage
• loss-of-function of the p53 tumor-
suppressor gene results in a malignant
carcinoma

8. Genes mutated
• Gain of functions : Proto-oncogenes
• Growth factors (I)
• Growth factor Receptors (II)
• Intracellular signalling pathway (III)
• Transcription factors (IV)
• Loss of fuction: Tumor Suppressor
genes
• Cell cycle control genes (V)
• DNA Repair genes (VI)
• Apoptotic genes (VII)

9. Proto-oncogenes -> Oncogenes
• Gain of function mutation
• Point mutation -> Amplification -> Constitutive expression
• Growth receptors
• EGFR, Her2
• Signal transduction
• K-RAS, B-RAF
• Chromosomal translocation
• BCR-ABL
• C-MYC-IGH

10. Tumor suppressor genes
• Inherited mutations
• Knudson two hit hypothesis
• Loss of heterozygosity
• Early onset
• Bilateral/ Multi-focal
• Sporadic mutation
• Loss of function of both alleles
• RB gene -> Retinoblastoma
• BRCA gene -> Breast Cancer
• APC gene -> Colon cancer

11. HISTORY OF ONCOLOGY - 4
Hallmarks of Cancer: The Next
Generation
Hanahan and Weinberg
Cell 144: 646 2011

12. BENIGN AND MALIGNANT TUMORS
Benign Malignant
1. Usually encapsulated Non encapsulated
2. Usually non invasive Invasive
3. Highly differentiated Poorly differentiated
4. Rare mitoses Mitoses relatively
common
5. Slow growth Rapid growth
6. Little or no anaplasia Anaplastic to
varying degrees
7. No metastases Metastases

13. Classification and Nomenclature
• Malignant tumors
– Named according to the tissues from which they arise
• Malignant epithelial tumors are referred to as
carcinomas
– Adenocarcinoma (from glandular epithelium)
• Malignant CT tumors are referred to as sarcomas
– Rhabdomyosarcomas (from skeletal muscle)

14. Classification and Nomenclature
• Cancers of lymphatic tissue are lymphomas
• Cancers of blood-forming cells are leukemias
• Carcinoma in situ (CIS)
• Epithelial malignant tumors that have not broken through BM or invaded the
surrounding stroma

16. Staging system : TNM
• Early – Stage I and II
• Locally advanced – Stage III
• Metastatic – Stage IV

17. Invasion and Metastasis
• Metastasis is the process by which a tumor cell leaves the
primary tumor, travels to a distant site via the circulatory system,
and establishes a secondary tumor

18. Preferential Metastatic site
Primary tumor Common distant site (s)
Breast’ adenocarcinoma Bone, brain, adrenal
Prostate adenocarcinoma Bone
Lung small cell carcinoma Bone, brain, liver
Skin cutaneous melanoma Brain, liver, Bowel
Thyroid adenocarcinoma Bone
Kidney clear cell carcinoma Bone, liver, thyroid
Testis carcinoma Liver
Bladder carcinoma Brain
Neuroblastoma Liver, adrenal

19. Reason for organ selectivity
Mechanistic theory: determined by the pattern of blood flow.
“Seed and soil” theory: the provision of a fertile environment in which
compatible tumor cells could grow.

20. Determining factors
• Appropriate growth factors or extracellular matrix environment.
• Compatible adhesion sites on the endothelial lumenal surface.
• Selective chemotaxis at which the organ producing some soluble
attraction factors to the tumor cells.

21. 5 major steps in metastasis
1. Invasion and infiltration of surrounding normal host tissue with
penetration of small lymphatic or vascular channels;
2. Release of neoplastic cells, either single cells or small clumps, into
the circulation;
3. Survival in the circulation;
4. Arrest in the capillary beds of distant organs;
5. Penetration of the lymphatic or blood vessel walls followed by
growth of the disseminated tumor cells.

23. Stages of metastasis
• Invasion : primary tumour cells enter circulation.
• Translocation of cells across extracellular matrix barriers.
• Lysis of matrix protein by specific proteinases.
• Cell migration.
• Circulation to the secondary site of tumour growth.
• Colonisation : formation of secondary tumour.

24. Cancer Etiopathogenesis
• Non-lethal genetic damage lies at the heart of carcinogenesis
• Genes implicated
• Proto-oncogenes
• Tumor Suppressor genes
• Genetic damage
• Inherited
• Environmental

25. Environmental Risk Factors
Increased Decreased
• Tobacco * Exercise
• Radiation * Proper Diet
• Ionizing
• UV
• Alcohol
• Bacteria and Viruses
• Diet
• Obesity
• Occupational Hazards

26. Environmental Risk Factors
• Tobacco
– Multipotent carcinogenic mixture
– Linked to cancers of the lung, lower urinary tract,
aerodigestive tract, liver, kidney, pancreas, cervix
– Smoking and Non-smoking form

27. Environmental Risk Factors
• Ionizing radiation
– Emission from x-rays, radioisotopes, and other
radioactive sources
– Exposure causes cell death, gene mutations, and
chromosome aberrations
– Bystander effects
– Poor gene repair
– Changes in gap junction intercellular
communication

28. Environmental Risk Factors
• Ultraviolet radiation
– Causes basal cell carcinoma, squamous cell
carcinoma, and melanoma
– Principal source is sunlight
– Ultraviolet A (UVA) and ultraviolet B (UVB)
– Promotes skin inflammation and release of
free radicals

29. Environmental Risk Factors
• Alcohol consumption
– Risk factor for oral cavity, pharynx,
hypopharynx, larynx, esophagus, and
liver cancers
– Cigarette/alcohol combination increases
a person’s risk

30. Environmental Risk Factors
• Bacterial
–Helicobacter pylori- Stomach cancer,
MALTOMA
• Viruses
– HPV – Cervical cancer and Oropharyngeal Cancer
– EBV – Nasopharyngeal Ca and Hodgkin lymphoma

31. Environmental Risk Factors
• Physical activity
– Reduces cancer risk
• Decreases insulin and insulin-like growth factors
• Decreases obesity
• Decreases inflammatory mediators and free
radicals
• Increased gut motility

32. Environmental Risk Factors
• Occupational hazards
– Substantial number of occupational carcinogenic
agents
• Asbestos
• Dyes, rubber, paint, explosives, rubber cement,
heavy metals, air pollution, etc.
• Radon

33. Cancer Incidence: India

34. Cancer Incidence : India

35. History of Chemotherapy
• Goodman and Gilman first administered nitrogen mustard to patients
with lymphoma
• nitrogen mustard was developed as a war gas rather than as a medicine
• toxic effects on the lymphatic system led to clinical trials

36. Chemotherapy
• Chemotherapy attacks tumors at the cellular level by interrupting processes or
inhibiting substances necessary for cellular replication and life
• During the cell cycle, there is replication of the entire genome and division of the
cell into genetically identical daughter cells
• Goals of Cancer Chemotherapy
• Cure
• Prolong survival
• Palliation
• Radiosensitive

37. Chemotherapy
• Cell cycle phase – specific
• agents with major activity in a particular phase of cell cycle
• schedule dependent
• Cell cycle phase – nonspecific
• agents with significant activity in multiple phases
• dose dependent

38. Conventional Chemotherapy

39. Chemotherapy classes
• Alkylating agents
• nitrogen mustards
• thiotepa, busulfan
• nitrosoureas, mitomycin
• procarbazine, dacarbazine
• Taxanes
• paclitaxel, docetaxel
• nab-paclitaxel
• Topoisomerase II inhibitors
• etoposide
• Platinum Complexes
• cisplatin, carboplatin
• oxaliplatin
• Anthracyclines
• doxorubicin, daunorubicin
• idarubicin, mitoxantrone
• Antimetabolites
• methotrexate
• purine antagonists
• pyrimidine antagonists
• Tubulin interactive agents
• vincristine, vinblastine
• Miscellaneous agents
• bleomycin
• asparaginase
• hydroxyurea

40. Chemotherapy in Breast Cancer

44. Adjuvant therapy in breast cancer
• All breast cancer patients need consideration of adjuvant therapy
• There are multiple possible treatment options which can be used individually
or combined
• Includes not only chemotherapy but endocrine and targeted therapy
• Who to treat with which agents….
• Prognostic factors
• Predictive factors

45. Predictive factors
• Hormone receptor status
• Estrogen receptor
• Progesterone receptor
• Her 2 Amplification

46. Without Systemic Treatment
• 1-3 LN: 25-35% recurrence rate
• 4-9 LN: 25-55% recurrence rate
• >10 LN: >70% recurrence rate

47. Chemotherapy regimen
1. CMF (Cyclophosphamide, Methotrexate, 5-FU)
2. AC (Doxorubicin, Cyclophosphamide)
3. FEC (5-FU, Epirubicin, Cyclophosphamide)
4. AC-docetaxel, AC-paclitaxel
5. Dose Dense AC
6. FEC-T

48. Nothing CMF regimen
Anthracycline
containing
regimen
Anthracycline AND
Taxane Containing
regimen

49. Endocrine therapy
• Hormone Receptors
• Oestrogen/ Progesterone
• Regulate gene expression through interaction with hormone response elements.
• Endocrine Therapy
• Tamoxifen and Aromatase inhibitors (Anastrazole/Letrozole)
• Reduces the risk of systemic recurrence
• Increased overall survival
• All women regardless of age, menopausal status, nodal involvement, tumour size, HER2
status or use of chemotherapy
• Therefore almost universal use across the population of HR +ve
patients

51. Targeting Her2
• Member of the epidermal growth
factor receptor tyrosine kinase
family
• EGFR-1, HER2, HER3, HER4

52. Her2 in breast cancer

53. Targeting Her2
• Trastuzumab (Herceptin)
• Adjuvant: survival advantage
• Side effect profile
• Modify cardiac muscles response to stress
• 5% of patients experience asymptomatic decrease in EF
• Increased risk with advanced age, HTN, poor initial EF
• HER2 is a tyrosine kinase receptor that activates downstream
oncogenic signaling pathways

54. Targeting Her2
• HER2/HER3 Dimers may provide an escape mechanism for
trastuzumab
• Therefore it has been postulated that a combination of HER2 receptor targets
may have synergistic effects
• Pertuzumab
• Shows survival benefit in neo-adjuvant and metastatic setting
TRASTUZUMAB PERTUZUMAB
Trastuzumab continually suppresses
HER2 activity
Inhibits HER formation of dimer pairs
Flags cells for destruction by the
immune system
Suppresses multiple HER signalling
pathways
Does not inhibit HER2 dimerization Flags cell for destruction by immune
system

55. Targeting her2: Antibody drug conjugate
• Trastuzumab emtansine and Trastuzumab deruxtecan

56. Chemotherapy in Leukemia
• Leukemias
• Acute Leukemia
• Chronic Leukemia
• Acute Leukemia
• Acute Myeloid Leukemia
• Acute Pro-myelocytic Leukemia
• Acute Lymphoblastic Leukemia

57. Acute Lymphoblastic leukemia
• Early lymphoid precursors (Lymphoid blasts)
• Replace normal haematopoetic cells
• Bone marrow failure

58. Treatment Outline
• Remission Induction – 4 to 6 weeks
• Intensification
• CNS Directed therapy
• Maintenance

59. Principle of chemotherapy in ALL
• Norton Simon hypothesis
• Rate of cell killing proportional to rate of tumor growth
• Dose dense treatment -> greater cell killing

60. Induction

61. Intensification
• High dose methotrexate
• Re-induction
• Steroids
• Vincristine
• Doxorubcin
• Consolidation
• Cytarabine
• Cyclophosphomide
• 6-Mercaptopurine
Maintenance
• 2 years
• 6 mercaptopurine
• Methotrexate

62. Acute Promyelocytic Leukemia
• Acute promyelocytic leukemia (APL) is a biologically and clinically
distinct variant of AML.
• AML-M3 in the older (FAB) classification
• acute promyelocytic leukemia with t(15;17)(q24.1;q21.2);PML-RARA
–WHO 2016
• 5-20% of AML (Blood. 2012;119(1):34.)
• 80-90% Cure rate

63. All trans retinoic acid
APL is characterized by the expression of PML/RARA that confers self-renewal
properties to committed cells and blocks promyelocyte differentiation.
in APL cells, PML/RARA heterodimerize with RXR and recruit corepressors into
master genes that control promyelocyte differentiation. RA releases
corepressors and recruits the coactivators, leading to transcriptional activation
of targets and differentiation.
Retinoic
acid RA also induces the recruitment of the proteasome that degrades PML/RARA.
RARA can also recruit methylating enzymes,leading to hypermethylation of the
down-stream gene promoter, resulting in aberrant epigenetic control at critical
gene chromatin domains.
caspase-mediated cleavage of the PML-RARAchimeric protein

64. Arsenic trioxide
• Arsenic enhances sumoylation of PML/RARA on Lys 160, which
modulates Daxx binding (and thus repression), but also triggers
SUMO-dependent polyubiquitination proteasome-dependent
degradation of PML and PML/RARA.
• This will modulate Daxx binding to PML/RARA, leading to the
release of transcriptional repression.
•

65. ATRA+ATO synergism
• Acts at different levels
• Amplifies RA signaling
• Activates Ubiquitin-proteasome pathway
• Downregulates Telomerase
• Induces phosphorylation of RXR
• cAMP/PKA mediated differentiation

66. Thank you