Introduction to Neoplasia, Pathology, and Chemotherapy

Definition of Neoplasm

New growth either benign or malignant

Definition of Tumor

lump or swelling

Definition of Cancer

any malignant neoplasm

“-plasias”

1) Hyperplasia

2) Metaplasia

3) Dysplasia

4) Anaplasia

increase in number of cells, substitution of cells, loss of normal architecture, and dedifferentiation

Origins of carcinoma

squamous epithelial cells

Origins of adenocarcinoma

glandular tissue

Origins of sarcoma

mesenchymal tissue like bone, muscle, fat

Origins of lymphoma and leukemia

hemapoietic tissues

Origins of melanoma

skin or eye

Origins of blastoma

precursor cells called blasts that are common in children

Origins of teratoma

germ cell made of several different cells

Tumor cells that are “well-differentiated” look like what?

normal

Tumor cells that are “poorly differentiated” or “undifferentiated” look like what?

abnormal

What using the clinical staging system for cancer, what does T/N/M stand for. X? 0?

Tumor, lymph nodes, and metastasis. X means not evaluated and 0 means no evidence

Hallmarks of Cancer (7)

Sustaining cell signaling, resisting cell death, genome instability and mutation, inducing or accessing vasculature, activating invasion and metastasis, enabling replicative immortality, avoiding immune destruction

What is defined as any gene in a healthy cell that is capable of promoting tumor growth? What does it arise from? What are 2 examples of an oncogene

Oncogene and it arises from proto oncogenes. v-Src and EGFR

How do you identify a tumor suppressor? How does it lose its tumor suppressor function? What are examples of tumor suppressors?

Loss of heterozygosity. Requires 2 hits to lose its tumor suppressor function. Examples are RB1 and BRCA

Activating oncogenes like EGFR can cause what

increase in signaling and sensitivity to EGFR inhibitors

Tumor Suppressor mutations can cause what?

Synthetic lethality, predicts susceptibility of chemotherapies likes PARP inhibitors

MOA of PARP inhibitors “-parib”

Traps PARP to DNA making it unable to uncouple from DNA

5- year survival rate of chemotherapy

69%

What are the stages of the cell cycle and the respective cyclins that control them plus what they blind to

G0/G1 controlled by cyclin D binds to CDK 4/6. S-phase controlled by cyclin A binds to CDK2. G2/M controlled by cyclin B binds to CDC2

What type of drug would be helpful in targeting cancer cells in G0?

Drugs that do not require cell cycling

What drug is effective against cycling cells?

Cell cycling non-specific

What drug effective for specific phases of the cell cycle?

Phase specific drugs

What is an example of combination therapy and what are its benefits?

CHOP and it increases cell kill, decreases likelihood of resistance, and manages toxicity profiles

What are the drug resistance mechanisms

Altered drug metabolism, changes in drug target or function, physiologic changes, and cell survival

What are the effects of altered drug mechanisms?

Increased efflux pumps like p-gp MRP. Decreased influx and activation of prodrugs. Increase detoxification

What are the effects of changes in drug target or function when it comes to drug resistance

increased gene amplification, mutations altering binding sites, and activation of redundant pathways

What are the effects of physiologic changes when it comes to drug resistance

brain metastasis so no BBB crossing, massive stromalization that impedes drug transport, and changes in cell state such as EMT

What are the effects of cell survival in drug resistance mechanisms?

Increased anti-apoptotic regulators and increased DNA repair capacity

Dose limiting toxicities from chemotherapy

hematopoietic, GI, n/v, and loss of appetite

Principle of combination chemotherapy

Use drugs that are individually effective, use drugs at maximal doses, and combine agents with different mechanisms or cell cycle phase specificities