Solid Tumor

Question 1

Cell Cycle

Answer 1

• Gap 0 (G0): Rest phase
• Gap 1 phase (G1): cell growth and DNA preparation for synthesis
  - produce RNA; required nitrogen supply + energy
• S-phase (synthesis): DNA replication
• Gap 2 phase (G2): further cell growth + mitosis preparation
  - assembly of microtubules; DNA assessed for damage (P53 immune suppressor)
• M Phase (mitosis): inhibit microtubule function + block topoisomerase (DNA unwinding) FXN

Question 2

Factor affecting multiple cycles

Answer 2

antitumor antibiotics

Question 3

50% of cancers

Answer 3

• breast
• prostate
• colon
• lung

Question 4

Neoplasms

• malignant
• benign

Answer 4

new growth

• unregulated growth of the cells, tissue invasion, and metasis (cancerous)
• lack ability to invade other tissues, little impact to overall health (benign)

Question 5

Carcinogenesis: Initiation

Answer 5

normal cell exposed to carcinogens –> causes genetic alterations (but not subject to just genetic alterations, ie: epigenetic alterations) –> DNA damage repaired + reversed by cell regulation mechanisms; proliferation can be reversed by apoptosis

-progression = irreversible as mutations are promoted + mutated cells accumulate

CANCER: selective growth advantage, clonal populations develop –> MULTIPLE MUTATIONS required for cancer (exception: BCR.ABC chronic myelogenous leukemia)

Question 6

Carcinogenesis: Initiation

• acquired
• inherited

Answer 6

• small cell lung cancer or Hodgkin lymphoma (Epstein Barr)

- BRCA 1/2 gene (ovarian risk, breast cancer in women) or Lynch syndrome (colon cancer, others)

Question 7

Types of Mutations:

• point
• frameshift
• missense
• nonsense
• duplication

Answer 7

• mutation involving substitution of a single base pair
• insertion or deletion of 1 or 2 base pairs so that
• a mutation that results in a change in the amino acid
• a mutation that results in a premature signal to stop building a protein
• results in multiple copying

Question 8

Common Initiation Mutations

Answer 8

–> activation of oncogenic pathways
-oncogenes: a gene that has the potential of causing cancer when activated
EX: growth factor receptors, proteins involved in cell cycle checkpoints
(EGFR, KRAS, ALK , BCL-ABL, others)
-EGFR mutation present in lungs and colon rectal cancers

–> inactivation of apoptotic pathways
-tumor suppressor genes
EX: receptors of inhibitory pathways, apoptotic proteins, mutations involving cell surface proteins
-P53 pathways: majority of cancers have mutations that affect p53
(APC, BRCA1, BRCA2)

• -> mutation repair pathways
• MMR: MLH1 in colorectal cancers

Question 9

Carcinogenesis: Promotion

Answer 9

altered environment to allow growth of altered cell populations

• promoters: chemicals that stimulate activation and proliferation
  - suppress the regulatory pathways/proteins
  - activate the growth pathways
• MITOGENIC: reversible, tumors may regress if stimuli removed

tumors are considered benign at this point
EX
- benign breast tumors
- polyps in colon

Question 10

Carcinogenesis: Conversion/Progression

Answer 10

multiple mutations accumulate creating a favorable environment
- chromosomal abnormalities, gene amplification, recombinations.

interactions with the microenvironment
- inflammation, blunting of immune responses, angiogenesis

ultimately leading to progression of cancer

Question 11

Progression from polyp to stage IV

Answer 11

cells become malignant depending on environment

antagonists:
- normal epithelium –> aberrant crypt foci: NSAIDS, folate, statins
- aberrant crypt foci –> small adenoma: NSAIDs, statins
- small adenoma–> large adenoma: NSAIDs, statins, AKT, EGFR inhibitors

promoters:
- aberrant crypt foci: COX-2 over expression
- aberrant crypt foci –> small adenoma: HMG-CoA R overexpression
- small adenoma–> large adenoma: caveolin-1, AKT over expression

Question 12

Benzopyrene and Lung Cancer

Answer 12

carcinogen found in cigarette smoke

• binds to DNA forming a covalent adduct
  - disrupts shape of DNA and alters transcription/translation –> transversion from a G:C base pair to A:T base pair
  - CpG islands: G:C rich regions that shut down gene translation

prolonged exposure=additive effects

Question 13

EGFR mutation and lung cancer

Answer 13

epidermal growth factor receptor (mutations result in gain of copy number)

• 10% of lung cancer = EGFR +; indolent course of lung cancer and sensitive to tyrosine kinase inhibitors
• develops resistants

Question 14

Colon Cancer and promoters

Answer 14

familial adenomatous polyposis (FAP)
-MUTYH mutation: tumor suppressor gene

cancer risk increases exponentially by age; many polyps don’t result in cancer
-COX2 over expression; treated with chemoprohylaxis (CELECOXIB: COX2 inhibitor)

Question 15

Estrogen and Breast Cancer

Answer 15

breast cancer is graded/treated on the following:

• presence of estrogen receptor/progesterone receptor
• human epidermal receptor-2 status
• BRCA status

estrogen=promoter
- overexpression of ER allows the cancer to respond to pro-growth signal; more ER = stronger response

adding anti estrogen or aromatase inhibitor can control breast cancer

• inhibitory molecules: without them it would result in proliferation
  
  • aromatase inhibitors, tamoxifen

Question 16

Luria and Delbruck

Answer 16

conducted experiment to understand how mutations arise in bacteria
result: number of resistant colonies varied significantly between plates
-resistance is due random mutations
cancer cells are no different: some are inherently resistant to a chemotherapy agent

Question 17

Goldie-Coldman Hypothesis

Answer 17

probability of resistance to a drug is greater as the size of a tumor increases and.or the rate of division increases

principles:

• tumors need to show sensitivity to each agent as a single agent
• drugs used in combination should have different mechanisms of action

Question 18

Inflammation and Cancer

Answer 18

immune system can recognize and eliminate cancerous cells –> cancer relies on inflammation and trick the immune system to survive

checkpoint pathways are essential for immune response:

• CTLA-4, PD-1, LAG-3, TIM-3
  
  • in cancer, cells up regulate checkpoint pathways

Question 19

Hodgkin’s lymphoma

Answer 19

Hodgkins cells turn up inflammation and turn off cytotoxic attacks on cancer cells

• NF-kB pathway, TNF-alpa pathways are unregulated
• inflammatory pathways recruit immune cells

Question 20

PD-1 and PD-L1 Inhibition

Answer 20

PD-1 inhibitors:
nivolumab (opdivo) –> lung cancer
pembrolizumab (keytruda)

PD-L1 inhibitors:
atezolizumab (tecentriq)
durvalumab(imfinzi)

-normally protects against excessive immune system stimulation

Question 21

Cancer Growth: Gompertzian growth

Answer 21

fraction of tumors progressing thru cell cycle influences susceptibility

as time increases:

- cells develop chemo resistance 
- competition over nutrients 
- fewer cells going through division

Question 22

Angiogenesis

Answer 22

development of new blood vessels

NORMALLY:
-induced by hypoxia–> damaged tissues will release pro-angiogenic factors into circulation (VEGF and PDGF)

CANCER:

- growth becomes dependent on nutrient supply:
       - blood supply becomes rate limiting step
       - cancers need blood and oxygen 

Target for drug therapy

Question 23

Metastases

Answer 23

As tumors get larger, cells are shed from tumor

• invasion of vasculature
• angiogenesis
  - degrade and detach from extracellular matrix

Circulating tumor cells (CTC): measurable cells circulating in the vasculature

colonies establish, extravasate and grow; specific cancers metastasize to common sites

Question 24

Staging of Cancer

Answer 24

staging utilizes a TNM description; staging does not direct therapy

stage 1: small tumor, local disease, goal:cure, o metastasis
stage 2: large tumor, local-regional disease, goal:cure, no metastasis
stage 3: small - large tumor, regional disease, goal: cure-palliation of symptoms, no metastasis
stage 4: small - large tumor, present metastasis, global disease, goal: palliation