PHRM 868 (Therapeutics IV) Exam 1 Flashcards
The majority of cancers are found where?
In the sex organs
Cancer occurs more in which population?
Older people
(age 65-74) (median age=67)
Why do older people develop more cancers?
People accumulate more genetic mutations as they age
(from more cell divisions and more exposures to toxic substances)
True or False: Cancer mortality is decreasing
True
Which cancer has had a massive increase in cases within recent years, making it the most common cancer?
Lung cancer
-due to the large increase in cigarette smoking in the 60’s
What is a neoplasm?
“New growth”
-May be benign or malignant
(can be cancerous or non-cancerous)
What is a tumor?
A nonspecific term to describe a lump or swelling
(can be cancerous or non-cancerous)
What is cancer?
Any malignant neoplasm (new growth)
What is hyperplasia?
An increase in organ or tissue size due to an INCREASE IN THE NUMBER OF CELLS
-can be physiologic, compensatory, or pathologic
What is metaplasia?
An adaptive, SUBSTITUTION of one type of adult tissue to another type of adult tissue
What is dysplasia?
An abnormal cellular proliferation in which there is LOSS OF NORMAL ARCHITECTURE
What is anaplasia?
A LOSS OF STRUCTURAL DIFFERENTIATION
(cells start to look the same)
-Cells dedifferentiate
-Frequently occurs in tumors
True or False: Normal epithelial cells are very organized
True
What is the site where lung cancer occurs?
Bronchial epithelium
What is a carcinoma?
Malignant neoplasm (new growth) of SQUAMOUS EPITHELIAL CELL origin
What is a papilloma?
A benign carcinoma
What is an adenocarcinoma?
Malignant neoplasm derived from GLANDULAR TISSUE
What is an adenoma?
A benign adenocarcinoma
What is a sarcoma?
Malignant neoplasm originating in MESENCHYMAL TISSUES or its derivatives
(ex: bone, muscle, fat)
Where is mesenchymal tissue found?
Bone, Muscle, Fat
What are lymphoma and leukemia?
Malignant neoplasms of hematopoietic tissues
(blood cells/ plasma)
What is melanoma?
Cancer of pigment producing cells
(ex: melanocytes in the skin or eye [uveal Melanoma])
What is blastoma?
Malignancies in precursor cells (AKA blasts)
-more common in children
What is a teratoma?
A germ cell neoplasm made of several different differentiated cell/tissue types
Leukemia is a cancer of which cells?
White blood cells of hematopoietic origin
Stage 0 in the Numerical Staging System of Carcinomas means what?
In situ carcinoma
*No sign of local invasion
-Has not gone outside of the tissue it is originally diagnosed in
Stage I in the Numerical Staging System of Carcinomas means what?
Microscopic invasion of surrounding tissue
Stage II in the Numerical Staging System of Carcinomas means what?
4-9 surrounding lymph nodes are involved
Stage III in the Numerical Staging System of Carcinomas means what?
10 or more surrounding lymph nodes are involved
The Numerical Staging System of Carcinomas is largely based on what 3 factors?
-Tumor Size
-Tumor Location
-Tumor Number
Stage IV in the Numerical Staging System of Carcinomas means what?
Distant metastases are detected
Primarily only which tumors get staged through the numerical staging system?
Solid tumors
True or False: Stage 4 cancer always means lethality
False
In the TNM staging system, what do T, N, and M stand for?
T: Primary Tumor
N: Regional Lymph Nodes
M: Distant Metastasis
What does “X” mean in the TNM staging system?
Cannot be evaluated
What does “0” mean in the TNM staging system?
No evidence/ No involvement
What does a Tis stage in the TNM staging system mean?
Carcinoma In Situ (CIS)
-abnormal cells are present but have not spread to neighboring tissue
-although not cancer, CIS may become cancer and is sometimes called preinvasive cancer
What does T1, T2, T3, T4 mean in the TNM staging system?
Represents the size and/or extent of invasion of the primary tumor
What does N1, N2, N3 represent in the TNM staging system?
Degree of regional lymph node involvement
(number and location of lymph nodes)
What does M1 in the TNM staging system mean?
Distant metastasis is present
Summary Staging includes what 5 main categories?
In Situ
Localized
Regional
Distant
Unknown
What is the In Situ Stage of summary staging?
Abnormal cells are present only in the layer of cells in which they developed
What is the Localized Stage of summary staging?
Cancer is limited to the organ in which it began, without evidence of spread
What is the Regional Stage of summary staging?
Cancer has spread beyond the primary site to nearby lymph nodes or tissues and organs
What is the Distant Stage of summary staging?
Cancer has spread from the primary site to distant tissues or organs or to distant lymph nodes
What is the Unknown Stage of summary staging?
There is not enough information to determine the stage
What is a tumor grade?
The description of a tumor assigned by a pathologist
What is a “well-differentiated” tumor?
The cells of the tumor and the organization of its tissue resemble those of normal cells and tissue
What is an “undifferentiated” or “poorly differentiated” tumor?
A tumor with abnormal-looking cells and which may lack normal tissue structures
True or False: “well-differentiated” tumors tend to grow and spread at slower rates than “undifferentiated/ poorly differentiated” tumors
True
What does a grade of GX mean?
Grade cannot be assessed (undetermined grade)
What does a grade of G1 mean?
Well differentiated (low grade)
What does a grade of G2 mean?
Moderately differentiated (intermediate grade)
What does a grade of G3 mean?
Poorly differentiated (high grade)
What does a grade of G4 mean?
Undifferentiated (high grade)
What are the 3 characteristics of cancer?
-Uncontrolled Cellular Growth
-Tissue Invasion
-Metastasis
Which characteristic of cancer is also a characteristic of benign tumors?
Uncontrolled cellular growth
True or False: For many tumors the growth of the primary tumor is not going to be life threatening
True
-Can become deadly when it moves out of these areas
What is RSV
Retrovirus
(integrates into the genome)
RSV encodes what oncogene?
v-Src
The oncogene v-Src is similar to which protein in the body?
Src
What was the first discovered example of an oncogene?
v-Src
What is a proto-oncogene?
Any gene in a healthy cell capable of promoting tumor growth
(not necessarily going to turn cancerous)
What is Alfred Knudsen’s 2-hit hypothesis?
For any tumor to develop, you need two mutations in a tumor suppressor gene for it to not work and to be able to develop a tumor (both alleles must be mutated). If you have one mutation you would only need one more, therefore you are more likely to develop the tumor. People with no mutations are less likely since they must develop two
-Heterozygous mutations can be inherited and families show increased susceptibility to cancers
(most tumor suppressors can be expressed from either chromosome which is why they need homozygous deletion/mutation to stop working)
What is retinoblastoma?
A childhood retinal cancer in which retinal cells do not stop dividing during development and form tumors
What is RB1?
Tumor suppressor
*this is the tumor suppressor gene affected in retinoblastoma
What is p16?
Tumor suppressor
-prevents moles from becoming cancerous
True or False: Carcinogen-induced cancers have lower mutation rates
FALSE
carcinogen-induced cancers have very high mutation rates
What are the two most common carcinogens that induce cancer?
Smoking
UV exposure
Mutations in the EGFR catalytic domain have what effect?
Increase the intensity and duration of signaling in response to ligand
What is “synthetic lethality”?
Loss of function mutations in tumor suppressor genes can predict susceptibility to chemotherapies
(if a normal cell has two genes, by targeting one the cell will still survive because the second gene is still active. If a tumor cell has already lost function of one gene, we can target the other and kill the tumor cell without killing the healthy cells)
What are BRCA1 and BRCA2?
Tumor suppressor genes
-encode for proteins involved in DNA repair
The nonfunctional mutant alleles of BRCA 1/2 are inherited as what?
Germline mutations
BRCA mutations in breast cancer increase susceptibility to what?
PARP inhibitors
(PARP repairs double-stranded DNA breaks, Base-excision repair)
Both PARP1 and BRCA are responsible for what?
DNA repair
PARP1= Base-excision repair
BRCA= Homologous Recombination
When both PARP1 and BRCA are blocked, what happens?
DNA cannot repair itself, cell dies
*this is why PARP inhibitors are useful in cancer cells that already have non-functioning BRCA genes
What kind of drug is Olaparib?
PARP inhibitor
What cancers is Olaparib used to treat?
Cancers with BRCA 1/2 mutations
What is the MOA of Olaparib?
Traps PARP to DNA
–is unable to uncouple from DNA and unable to repair strand breaks
What is the current 5-year cancer survival rate overall?
69%
True or False: No cancers are currently curable by chemotherapy
False, but only a small number are
What are the 2 defining features of chemotherapies?
Non-specific
Toxic to cells
What is the Central Dogma of Biology
DNA (replicates) -> Transcription -> RNA -> Translation -> Protein
What happens in G0 of the cell cycle?
No division
What happens in G1 of the cell cycle?
Cell is quiescent or accumulating “building blocks” required for division
What happens in S of the cell cycle?
Cell replicates DNA
What happens in G2 of the cell cycle?
Cell assembles machinery for chromosomal segregation and cytokinesis
What happens in M of the cell cycle?
Mitosis
The cell cycle is controlled by what?
Cyclins paired with cyclin-dependent kinases
What is the R point?
The restriction point, this is the critical time point when cells decide whether or not to enter the cell cycle
What are cell cycle checkpoints?
Decision points where cells decide to proceed through the cell cycle
The G1 to S checkpoint in the cell cycle checks for what?
Do you have what you need to be able to double DNA?
(ensures the integrity of the genome)
-Is there a mitogenic signal telling the cell to proceed through the cell cycle?
-Are there sufficient quantities of the required nucleotide “building blocks”?
-Is there unrepaired DNA damage?
The S to G2 checkpoint in the cell cycle checks for what?
-Has the genome been replicated?
-Are there any errors (that have been made in doubling the DNA)?
The G2 to M checkpoint in the cell cycle checks for what?
-Have sister chromatid arms been separated?
-Has the machinery required for chromosomal segregation and cytokinesis been assembled?
Proteins that drive the cell cycle can act as what?
Oncogenes
Proteins that halt the cell cycle can act as what?
Tumor suppressors
What is P53?*
Tumor suppressor
“guardian of the genome”
What checkpoint does P53 affect?
G2
What is the function of RAS or KRAS?*
Give a strong signal to divide
(common oncogenic mutation)
What checkpoint does RAS or KRAS affect?
G0
What is RB1?*
Tumor suppressor
What is P16?
Tumor suppressor
What are the 2 master regulators of cell cycle initiation?
Cyclin D
CDK 4,6
What are mitogens?
Things that promote growth
(include estrogens, tyrosine kinases, etc)
What is the function of CDK 4/6?
-Master regulator of cell cycle initiation
-Phosphorylates RB1 (tumor suppressor) causing it to no longer work, this increases cell division
What kind of drug is Palbociclib?
CDK 4/6 kinase inhibitor
Is Palbociclib a targeted therapy?
No -targets all replicating cells
What cancers is Palbociclib approved to treat?
Cancers arising due to BRCA 1/2 mutations
Why are common chemotherapies selective for cancer cells?
-Tumor cells have lost cell cycle control mechanisms
(have increased cell proliferation)
(checkpoint controls are often lost as well!)
*Cancer cells do not fully repair damaged DNA, repair damaged mitotic spindles, or finish replicating DNA before proceeding to the next stage of the cell cycle
Opportunity: loss of checkpoint control results in increased cell death with chemotherapy
What happens to the cell cycle in cancer cells treated with chemotherapy that have lost G1/S checkpoint control?
-Cells do not halt in G1 and attempt to replicate damaged DNA
-This can trigger apoptosis
-If the cell has lost its apoptotic response, the cell replicates the damaged DNA and acquires lethal genetic damage that results in necrosis (cell death resulting in lysis and inflammation)
DNA alkylating agents are able to target cells in which stage of the cell cycle?
DO NOT REQUIRE CELLS TO BE CYCLING
-Are effective against cancer cells resting in G0 AND cells progressing through the cell cycle
What are some examples of cell cycle non-specific drug classes?
-Alkylating agents
-DNA intercalation agents
What does it mean for a drug to be cell cycle non-specific?
-They are most effective when the tumor cells are progressing through the cell cycle
-These drugs are not dependent upon the cell being in a specific phase of the cell cycle
-Many of these agents have some efficacy against cells resting in G0, but are more effective against cells progressing through the cell cycle
What does it mean for a drug to be phase-specific (or schedule-dependent)?
-They are most effective against tumor cells in a specific phase of the cell cycle
-They affect cellular events that occur within a specific phase of the cell cycle (ex: DNA synthesis, mitosis)
What is a limitation associated with phase-specific (or schedule-dependent) drugs?
The number of cells killed is limited to the number of cells present in the appropriate phase of the cell cycle
Higher doses of the drug may not result in greater tumor cell killing
Increased cell killing requires prolonged drug exposure
What are the major dose-limiting toxicities associated with chemotherapies?
Hematopoietic: WBC (granulocytes)- infections, Platelets- hemostasis, RBC- anemia
Gastrointestinal: Nausea & vomiting, loss of appetite
Cancer chemotherapy kills a constant ____, not a constant _______, of tumor cells
Cancer chemotherapy kills a constant fraction, not a constant number, of tumor cells
(it is impossible to kill all tumor cells with a single dose of drug, it will select for cells resistant to drug)
What is the Norton-Simon hypothesis for chemotherapy?
Give as dose-intensive and as early as possible
-Give chemotherapy at shorter intervals
-Use combination drugs with distinct mechanism of action
Why:
-Chemotherapy selects for cells resistant to the drug
-As tumor cells grow, their doubling time slows (remember most anticancer agents work on cycling cells)
-When the tumor burden decreases, the remaining cells re-enter exponential growth
-Diminishing returns: resistant and/or intolerable side effects
What factors increase the success rates of chemotherapies?
-Small tumor size
-Early diagnosis
-Increased drug intensity
True or False: Individual drugs in combination should be used at maximal doses
True
What is a commonly used combination of drugs in combination chemotherapy?
CHOP
-Cyclophosphamide (alkylating agent)
-Doxorubicin (anthracycline)
-Vincristine (microtubule inhibitor)
-Prednisone (steroid)
What are the advantages of combination chemotherapy?
-No additive toxicity for drugs with non-overlapping toxicities
-Increased cell killing
What are the possible ways that tumors initially sensitive to chemotherapy can become resistant?
-Altered drug metabolism
-Changes in drug target or function
-Physiological changes that promote resistance
What are the ways that tumors can alter drug metabolism to become resistant to chemotherapy?
-Increased transport of drugs out of the cell through efflux pumps
-Reduced transport into the cell
-Decreased activation of prodrug
-Increased detoxification of drug molecule
-Cell survival mechanisms
How can changes in drug target or function lead to tumors becoming resistant to chemotherapy?
-Increased expression of drug target through gene amplification or expression (upregulation of target makes it harder to inhibit)
-Emergence of mutant, structurally altered target (mutants are still active but do not bind the drug)
-Emergence of cells bearing alterations in genes whose products are functionally redundant with the drug target (cells can rewire pathways to bypass the need for the drug target)
What physiological changes can occur to tumors that make them more resistant to chemotherapy?
-Refuge of cancer cells in drug-protected anatomical sites (ex: metastasis to the brain where drugs do not cross the blood-brain barrier)
-Massive stromalization (structure impedes drug transport)
-Changes in cell state such as EMT (epithelial mesenchymal transition) (slows cell cycle, increases drug efflux pumps and increases anti-apoptotic proteins)
What cell survival mechanisms may allow a tumor to become resistant to chemotherapy?
-Activation of anti-apoptotic regulators (prevent cell death)
-Increased repair of damage caused by chemotherapies (most commonly the repair of drug-DNA adducts or DNA damage)
True or False: Chemotherapy is a narrow therapeutic index drug
True
What are the roles of glucocorticoids in cancer treatment?
-Have anti-cancer effects in the treatment of blood cancers
-Used as palliative care to: reduce inflammation, edema, and manage pain during chemotherapy
-Reduce hypersensitivity reactions, nausea, vomiting, and immune-related adverse effects
What are the 3 commonly used glucocorticoids?
Methylprednisolone
Prednisolone
Dexamethasone
What are the roles of hormonal therapies in cancer treatment?
*Disease specific- only for hormone-dependent cancers
(ex: breast, prostate, endometrial cancer)
Hormonal therapies target what?
Estradiol (breast, endometrial) and Dihydrotestosterone (prostate)
Where are the hormones targeted by hormonal therapies produced?
Adrenal glands
Ovary
Testis
Adipocytes
True or False: Hormonal cancers are considered more treatable cancers
True
-because we can target these cancers
What are the 2 strategies for endocrine therapy?
- Stop steroid receptor function
- Decrease production of steroids
Where is Gonadotropin-Releasing Hormone (GnRH) produced?
Hypothalamus
Where is LH/FSH produced?
Anterior pituitary gland
