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
If a patient has measurable estrogen receptors (ER) or progesterone receptors (PR) in their tumor, what does this mean for their prognosis?
It is a better prognosis because these receptors can be targeted
(high correlation between the presence of estrogen receptors and the likelihood of response to hormone therapy)
(Even stronger for ER+/PR+ tumors)
Which tumors are more likely to have estrogen receptors (ER+): poorly differentiated or well differentiated tumors?
Well differentiated tumors
-poorly differentiated tumors have higher growth fractions and are generally more sensitive to cytotoxic agents (chemotherapy)
True or False: Hormone therapy in breast cancer is generally limited to ER+/PR+ tumors
True
P450scc changes cholesterol to what?
Pregnenolone
Which enzyme creates dehydroepiandrosterone?
17, 20 lyase
Which enzyme converts testosterone to dihydrotestosterone?
5a-reductase
Which enzyme converts Androstenedione to Estrone and Testosterone to Estradiol?
Aromatase (CYP19)
(converts androgens to estrogens)
What is the first line treatment for ER+ tumors?
Endocrine therapy
What range of ER positivity is usually considered for endocrine therapy?
10%
(ER status can be heterogeneous)
Breast cancer is made up of 4 distinct diseases, what are they?
Luminal A/B
HER2-enriched
Basal-like
Claudin-low
ER+ tumors typically fall into which disease of breast cancer?
Luminal A/B
HER2 amplicon normally fall into which disease of breast cancer?
HER2-enriched
BRCA1 mutations normally fall into which disease of breast cancer?
Basal-like
Triple Negative Cancers (no estrogen, progesterone, or HER2) typically fall into which disease of breast cancer?
Claudin-low
Triple Negative Cancers (no estrogen, progesterone, or HER2) are typically treated with what?
Cytotoxic therapy (chemotherapy)
What common ending do the SERMs have?
“fene”
What are the 4 SERMs? (selective estrogen modulators)
Tamoxifen
Toremifene
Clomiphene
Raloxifene
What common ending do the SERDs have?
“trant”
What 2 drugs are SERDa?
Fulvestrant
Elacestrant
What kind of drug is Tamoxifen?
SERM
True or False: Tamoxifen is a prodrug
True
What must Tamoxifen be metabolized to in order for it to work? (must be metabolized to non-prodrug state)
4-OH-TAM
Which enzyme is responsible for the conversion of Tamoxifen to the high-affinity metabolite 4-OH-TAM?
CYP2D6
How does being a CYP2D6 poor metabolizer affect Tamoxifen use?
Do not recommend Tamoxifen for these patients because they will be metabolized to a much less powerful form and the drug will not be as strong
Tamoxifen binding to estrogen receptors will affect what?
Translocation
DNA binding
*in a tissue-specific manner
Tamoxifen has both antagonist and agonist effects, what are its antagonist effects on estrogen?**
-Blocks estrogen-dependent breast cancer cell proliferation
-Hot flashes (due to anti-estrogen effects)
Tamoxifen has both antagonist and agonist effects, what are its agonist effects on estrogen?
-Increased incidence of endometrial cancer
-Preserved bone density in postmenopausal women
Can Tamoxifen be used in premenopausal, postmenopausal, or both women?
Both!
What tumors are Tamoxifen primarily used to treat?
ER+/PR+ breast cancer
*Also metastatic ER+/PR+ breast cancer
First drug approved for breast cancer prevention in high-risk patients***
What is a benefit to using the SERM Raloxifene over Tamoxifen?
No endometrial hyperplasia
What kind of drugs are Fulvestrant and Elacestrant?
SERDs (Selective Estrogen Receptor Down-modulator)
Do Fulvestrant and Elacestrant act as antagonists or agonists?
Antagonists
(no agonist effects)
(full antagonist at high doses)
Which SERD is taken po and which is taken IM?
Fulvestrant= IM
Elecestrant= PO
What are SERDs approved to treat?
ER+ metastatic breast cancer in postmenopausal women who have progressed on other antiestrogen therapy
Can SERDs treat premenopausal, postmenopausal, or both women?
Postmenopausal only
What cells act as a source of estrogen in postmenopausal women?
Adipocytes
Aromatase inhibitors that block the conversion of androgens to estrogens target what?
Peripheral tissue (adipose tissue)
NOT THE OVARY
What is the primary application of aromatase inhibitors and who is this used in?
Application: Estradiol suppression in postmenopausal women
What are the 2 imidazole-based non-steroidal aromatase inhibitors?
Anastrozole
Letrozole
What is the MOA of Letrozole and Anastrozole?
Potent and selective COMPETITIVE inhibitors of aromatase activity
Are Letrozole and Anastrozole used in premenopausal, postmenopausal, or both women?
Postmenopausal
What are Letrozole and Anastrozole used to treat?
Breast cancer
-either first line or can be started after 3-5 years of tamoxifen
*Note that these drugs show increased bone density loss compared to tamoxifen
What is the steroidal aromatase inhibitor drug?
Exemestane
Exemestane is structurally related to what?
Androstenedione (“suicide inhibitor”)
What is the MOA of the steroidal aromatase inhibitor Exemestane?
Acts as a false substrate that aromatase converts to a reactive intermediate
This intermediate binds irreversibly at the active site and inactivates the enzyme
What is the indication for Exemestane?
Treats estrogen-responsive breast cancer in postmenopausal women who have progressed on antiestrogen therapy
Is Exemestane used in premenopausal, postmenopausal, or both women?
Postmenopausal women only
LH activates which enzyme?
Chol-SCC
*this converts cholesterol to progesterone to corticosteroids
FSH activates which enzyme?
Aromatase (CYP19)
How do the Gonadotropin Releasing Hormone analogs work? (GnRH analogs)
They are peptide analogs of the neurohormone GnRH with modified amino acids to increase potency and reduce degradation
Create chronic stimulation of the GnRH receptors in the pituitary which eventually shuts them off leading to decreased aromatase and decreased estrogen
*Get a “flare” for 2-3 weeks at the beginning where estrogen increases before shutting off (originally increases tumor size)
Available in a depot formulation suitable for slow-release
What are the GnRH analogs?
Leuprolide acetate
Goserelin
What are the side effects of Leuprolide acetate and Goserelin?
-Transient worsening of symptoms due to initial increase in estrogen
Long term:
-Hot flashes
-Sexual dysfunction
*side effects are typical of antiestrogenic effects (menopausal)
Are GnRH analogs used in premenopausal, postmenopausal, or both women?
PREMENOPAUSAL
What is the indication for Leuprolide acetate and Goserelin?
Premenopausal breast cancer
What are the treatment options for premenopausal women with breast cancer?
GnRH agonists
Tamoxifen (SERM)
Surgical oophorectomy
What are the treatment options for postmenopausal women with ER+ breast cancer?
Tamoxifen (SERM)
Nonsteroidal aromatase inhibitors
Steroidal aromatase inhibitors
Pure anti-estrogens (SERDs)
What is the Gleason Score used for in prostate cancer and what does a higher or lower score mean?
Used to stage prostate cancer based on how well differentiated or undifferentiated the cancer is
Lower number= Well differentiated (1)
Higher number= Poorly differentiated/More cancer cells (5)
*Which enzyme is responsible for the conversion of testosterone to dihydrotestosterone (DHT)?
Type II 5-a reductase
Where does dihydrotestosterone bind in prostate cells?
Androgen Receptor (AR)
*note: this binding results in translocation to the nucleus and activates genes that drive cell growth
Where is the androgen receptor (AR) located?
Cytoplasm
How can prostate cancer affect the androgen receptor (AR)?
AR can be amplified in prostate cancer
What range of Prostate Specific Antigen (PSA) indicates prostate cancer?
> 6.5 ng/ml
Besides breast cancer, what other indication do the GnRH analogs Leuprolide acetate and Goselerin have?
-Palliative treatment of advanced prostate cancer
-Chemical castration within 3-4 weeks
What are the side effects of GnRH analogs (Leoprolide acetate and Goselerin) in men?
Gynecomastia
Decreased sexual dysfunction
*Get a flare of symptoms at start of treatment
What are the GnRH antagonists used in prostate cancer?
Degarelix
Relugolix
What are the GnRH antagonists (Degarelix and Relugolix) used for?
Advanced prostate cancer with need for androgen deprivation therapy
What is a benefit to using GnRH antagonists (Degarelix and Relugolix)?
Will not cause a flare of testosterone production like the analogs do
What is the main goal of treatments for prostate cancer?
To stop the production of dihydrotestosterone (DHT)
Which drug functions as a steroid analog?
Abiraterone
What is the MOA of Abiraterone?
Inhibits the function of 17 a-hydroxylase and C17,20 lyase
(CYP17 catalyzes the conversion of pregnenolone and progesterone to DHEA and androstenedione)
What is a common side effect of Abiraterone?
Increased cholesterol levels
What are the mechanisms of resistance to endocrine therapy seen in prostate cancer?
-Mutations in androgen receptors (AR) can result in androgen independent activation and prevent binding of AR antagonists
(referred to as Castration Resistant Prostate Cancer (CRPC))
What affect does signal transduction through kinases have on cancer?
Drives cancer proliferation
*kinases= mitogenic signaling (tell cells that they should divide)
*we want to target kinases with kinase inhibitors
What is the substrate that ALL kinases use?
ATP
What gets tested via PCR from lung biopsies to determine if a patient has a particular mutation of EGFR?
Genomic DNA
*if positive, these patients go on anti-EGFR therapies
Cell signaling is largely driven by what?
The transfer of phosphates
(ATP is the major source of the phosphate group that will be transferred by a kinase to a target protein)
What are the common targets for phosphorylation by kinases?
*Tyrosine
Serine, Threonine, Lipids
(nucleophilic substances)
What do phosphatases do?
Have the opposite action of kinases
*Remove phosphorylation
Note: cancers often show deletion of phosphatases
What is included in the general structure of a kinase?
N- and C- lobes connected by a hinge region
Activation loop that controls access to the active site
How many types of reversible kinase inhibitors are there?
3
What is a Type I kinase inhibitor?
Binds to the active conformation of the kinase
What is a Type II kinase inhibitor?
Binds to and stabilizes the inactive conformation of the kinase
What is a Type III kinase inhibitor?
Occupy an allosteric pocket outside of the ATP-binding pocket
(is the only one that does not bind to the ATP-binding pocket)
How do competitive kinase inhibitors work?
They bind the kinase in a reversible fashion and must compete with ATP for binding
How do covalent kinase inhibitors work?
They bind covalently with a reactive nucleophilic cysteine residue proximal to the ATP-binding site
-this results in blockage of the ATP site and irreversible inhibition
What patients will likely respond well to EGFR inhibitors?
Those with mutations in EGFR that cause it to be constitutively activated
How does EGFR affect cancer?
-Functions through tyrosine kinase
-EGFR signaling induces cell proliferation
-EGFR is over expressed and has higher signaling activity in many cancers
-Overexpression of EGFR correlates with a poor prognosis
What is the MOA of Gefitinib/ Erlotinib?
Small molecule reversible inhibitors of EGFR tyrosine kinase
-Competitively inhibit the enzyme by binding to the ATP binding site in the kinase domain
-Inhibition of the kinase activity turns off the signal to proliferate
What are Gefitinib/Erlotinib used to treat?
Patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 or 21 mutations
What is Afatinib?
Covalent inhibitor of all ErbB receptors
What does Afatinib treat?
EGFR mutant non-small cell lung cancer (NSCLC) with EGFR mutations
Therascreen Kit has been approved for detection of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations
Mutations in what can cause resistance to Geftinib?
T790M
When a T790M mutation occurs, and Gefitinib can no longer be given to treat NSCLC, what drug can be used in its place and act like a new “key” to fit this change?
Osimertinib
What is Osimertinib?
3rd generation EGFR inhibitor
Covalent kinase inhibitor
Effective against the T790M mutant EGFR that makes Gefitinib no longer work
What are the two ErbB molecules?
EGFR (ErbB1)
HER2 (ErbB2)
How is HER2 affected in breast cancer?
Genomically amplified in breast cancer
-Forms hetero/homo dimers that activate signal transduction without a ligand binding
*note: forms a heterodimer with EGFR
What is the normal function of HER2?
Growth Factor
-sends signals to cells telling them to grow and divide (Same as EGFR)
What is Lapatinib?
Small molecule, reversible, tyrosine kinase inhibitor that blocks both HER2 and EGFR signaling
(these molecules often work together so this is good)
What is Lapatinib used to treat?
HER2+ breast cancer
Combination with capecitabine: Treatment of advanced metastatic breast cancer in patients who have progressed on other therapies
What is the action of Tucatinib?
Small molecule tyrosine kinase inhibitor
*Preferentially binds HER2
What is Tucatinib used to treat?
HER2+ breast cancer
What is a benefit of using Tucatinib over Lapatinib?
Reduced adverse reactions
(potentially due to increased HER2 specificity)
What mutation is common in acute myeloid leukemia?
FLT3 mutations
either an internal tandem duplication (ITD, more common) or an activating mutation in the tyrosine kinase domain (less common)
*These mutations lead to increased proliferation and decreased apoptosis
What is FLT3?
A ligand that is a cytokine receptor important for hematopoietic cell survival and proliferation
What is Midostaurin?
First generation FLT3 inhibitor
(broad kinase inhibitor)
-Used to treat FLT3 mutations in Acute Myeloid Leukemia
What is Crenolanib?
Second generation FLT3 inhibitor
(more specific)
-Used to treat FLT3 mutations in Acute Myeloid Leukemia
What is Quizartinib?
Type II FLT3 inhibitor
**Specifically used for internal tandem duplication (ITD) mutations of FLT3 in Acute Myeloid Leukemia
What critical part of tumor formation is VEGFR involved in?
Angiogenesis
(and it drives tumor cell growth)
*important possible target
What is the Philadelphia chromosome (Ph1) and how does it contribute to cancer formation?
Part of one protein is combined (translocated) with part of another protein (“Frankenstein protein”), this leads to cancer
The 5’-portion of the Bcr gene combines with the 3’-portuon of the Abl gene
A chimeric transcript is produced called Bcr-Abl
What % of chronic myeloid leukemia is the Philadelphia chromosome (Ph1) found in?
95%
How does Bcr-Abl cause cancer?
It is a chimeric protein that is constitutively active
*note that Abl is a tyrosine kinase
What is Imatinib?
Type II small molecule inhibitor of the Abl tyrosine kinase
What is the result of inhibiting the Abl tyrosine kinase?
Reduced proliferation
Enhanced apoptotic cell death
What is Imatinib used to treat?
Chronic Myeloid Leukemia (CML)
Which type of medication must patients be on for life?
Abl inhibitors
*note that resistance is a lifelong battle
What is Ponantinib?
BCR-Abl inhibitor
-Effective against all major mutant forms of BCR-Abl
What mutation is considered the “gatekeeper” mutation and is resistant to all but one BCR-Abl compound?
T315I
What drug can be used to inhibit the T315I mutation?
Ponatinib
What role does the EML4-ALK translocation play in cancer?
Wild type ALK is a transmembrane receptor tyrosine kinase similar to EGFR
When ALK and EML4 inappropriately fuse, it becomes cytoplasmic and constitutively active
*Occurs in non-small cell lung cancers
What is Dabrafenib?
Second generation BRAF-V600 inhibitor
What is Alectinib?
Specific inhibitor of ALK
What is Alectinib indicated to treat?
Patients with anaplastic lymphoma kinase (ALK+) metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib
What drug is Dabrafenib commonly used in combination with and what do they treat?
Used in combination with Trametinib to treat BRAF V600E/K mutant metastatic melanoma
*combination seems to stem induction of squamous cell carcinomas by activated wild type BRAF
*Also used for NSCLC that have BRAF-600 mutations
What type of cancer with Ras and GRAF-V600 mutations does not tend to respond o Dabrafenib?
Colorectal cancer
What is Trametinib?
Type III allosteric inhibitor (first approved)
Inhibits the kinase activity of MEK1 and MEK2
What is a limitation to the use of Trametinib?
Not indicated for treatment of patients who have received prior BRAF inhibitor therapy
What is the most common side effect of Trametinib?
Rash
How does Acalabrutinib work?
Covalent BTK inhibitor
-Also targets Cys481
*More potent and selective than 1st generation ibrutinib
What is Acalabrutinib indicated for?
B-cell lymphoma
What is Sirolimus?
Inhibits the function of mTOR (a serine-threonine kinase)
What is the role of Sirolimus in cancer treatment?
Inhibits the immune response by blocking IL-2 signal transduction
(immunosuppressant -such as with organ transplants)
True or False: Kinase inhibitors cure patients
FALSE
-resistance is a major problem with these medications
-keep a patient in remission and the hope is they will die of something else before the cancer comes back
How do antimetabolites work?
Mimic the natural cellular substrates/cofactors (metabolites) that enzymes act on (they are analogs)
*Most of these are enzyme inhibitors
Block production of nucleotide building blocks required for DNA replication and transcription
-Target intermediary metabolic pathways involved in synthesis of essential molecules in proliferating cells
*Most require biotransformation to nucleotide analog (sugar and phosphate) to generate active species
Which part of the cell cycle do antimetabolites target?
S
(DNA replication)
*What is the most common dose-limiting side effect of drugs that are toxic to rapidly proliferating cells?
Myelosuppression
What is a nucleobase?
Just a single base
What is a nucleoside?
Base + Sugar
What is a nucleotide?
Base + Sugar + Phosphate
Most antimetabolites are nucleobases or nucleosides even through many enzymes use nucleotides. Why is this?
The phosphate group on the nucleotide cannot go through cell membranes
Therefore, antimetabolites are normally nucleobases or nucleosides that get converted to nucleotides inside of the cell
Which two nucleobases are purines (big molecules)?
Adenine
Guanine
What are the 2 functions of pyrimidine analogs?
-Interfere with pyrimidine nucleotide synthesis
(5-FU + Capecitabine)
-Inhibit DNA polymerase
(Ara-C + Gemcitabine)
*note: can also incorporate into DNA and RNA and interfere with function and replication
What is the primary function of uridine analogs?
Inhibit thymidine synthesis from uracil
(blocking this step causes you to have no thymidine and ultimately no DNA)
What kind of drug is 5-Fluorouracil (5-FU)?
Fluorinated uracil analog
-Uridine analogs inhibit thymidine synthesis from uracil
What active species is 5-Fluorouracil (5-FU) converted to?
Fluorodeoxyuridine monophosphate (Fdump)
*note: this is a nucleotide
How is thymidine normally synthesized?
When folates are present:
-Thymidylate synthase synthesizes thymidine monophosphate (TMP) from deoxy uridine monophosphate (dUMP)
-The hydrogen on dUMP gets replaced with a methyl on TMP
*Note: folate acts as a methyl donor
*Note: this mechanism is dependent on being able to pull a hydrogen off of dUMP and exchange it with a methyl to make TMP
*Note: Urine gets converted to thymine
How does FdUMP inhibit thymidine synthesis?
-Fdump mimics dUMP
-Binds the active site of thymidylate synthase
-The hydrogen is replaced with a Fluorine and cannot be pulled off to replace with a methyl
-The reaction cannot go to completion and thymidylate synthase is trapped
-TMP cannot be produced and DNA synthesis is inhibited “thymineless death”
How can toxicity with FdUMP be overcome?
Use thymidine treatment as rescue therapy
(because FdUMP depletes thymine levels)
What kind of inhibitor is FdUMP?
Covalent
What genetic variability makes some patients more susceptible to toxicity with use of 5-Fluorouracil (5-FU)?
Deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) which breaks down 5-FU
What drug has synergy with 5-Fluorouracil (5-FU)?
Leucovorate
(folate cofactor converted to tetrahydrofolate in cells)
(more tetrahydrofolate means that there is more covalent ternary complex with thymidylate synthase for the drug to bind)
What is the main function of cytosine analogs?
Inhibit DNA synthesis
What active species is Cytarabine converted to and how does it work?
Ara-CTP
-competitive inhibitor of DNA polymerase a
What genetic variability can lead to toxicity of Cytarabine?
Cytidine deaminase converts cytarabine to non-toxic uracil arabinoside
*Decreased levels of cytidine deaminase in the CNS increase toxicity in the brain and spinal cord
Which molecule has synergy with Cytarabine?
Tetrahydrouridine
-acts as a cytidine deaminase (CDA) inhibitor, preventing drug conversion to a non-toxic form
What is the main function of purine analogs?
Inhibit purine biosynthesis
What is 6-Mercaptopurine?
Purine analog
(adenine analog)
What is the function of 6-Mercaptopurine?
Inhibits multiple enzymes in de novo purine biosynthesis
blocks synthesis of purine nucleotides
Loss of function of which molecule can lead to 6-Mercaptopurine toxicity?
Thiopurine methyl transferase (TPMT)
(this molecule inactivates 6-MP)
What drug does 6-mercaptopurine interact with and what is the interaction?
Allopurinol
-Drug used to treat gout
-Xanthine oxidase is the enzyme that breaks down 6-MP
-Allopurinol is a xanthine oxidase inhibitor
-Leads to toxicity of 6-MP, cannot take these drugs together
What is the role of folate?
-Essential vitamin (B9)
-Used in synthesis of thymidine from uridine
-Acts as a methyl donor
-Reduced to tetrahydrofolate by dihydrofolate reductase (DHFR)
-DHFR inhibition inhibits thymidine monophosphate (TMP) synthesis
How does Methotrexate work?
Folate analog
-binds and inhibits DHFR to inhibit thymidine monophosphate synthesis
-this inhibits RNA and protein synthesis + purine and pyrimidine synthesis
What medication can be used to rescue from a methotrexate overdose?
Leucovorin
(serves as folate)
What are the 2 roles of Leucovorin?
Increases effects of 5-FU
Rescue for Methotrexate toxicity
What is the basic function of alkylating agents?
Generate electrophilic (electron deficient) intermediates that react with nucleophilic (electron rich) groups on DNA and proteins
-Attach alkyl group to DNA and protein
-Alkylate purine bases in DNA
What is the most common site of alkylation in purines by alkylating agents?
Guanine N7
What were the earliest alkylating agents?
Mustard Gas
What are alkylating agents used to treat?
Leukemia and Lymphoma
(because they kill off the immune system)
What are the effects of DNA alkylation?
Intrastrand linking between two bases on the same strand
Interstrand cross-linking of two separate strands
*these effect the double helix shape of DNA and cause it to no longer be recognized by enzymes for replication/transcription
What molecule in the body acts as a good nucleophile and can therefore cause resistance to alkylating agents by quenching their activity?
Glutathione
What are the side effects associated with alkylators?
-Mutagenic: cause lots of DNA damage and may form other cancers (second malignancies)
-Target rapidly dividing cells
-Myelosuppression
-Nausea
-Vomiting
-Carcinogenic
-Teratogenic
What is Chlorambucil?
Alkylating agent with additional aryl group to decrease the nucleophilicity of the nitrogen
(stabilized)
What is Cyclophosphamide?
Alkylating agent that is a prodrug and requires hydrozylation
What enzyme hydroxylates Cyclophosphamide?
CYP P450
What enzyme inactivates Cyclophosphamide?
Aldehyde dehydrogenase
*note: there are higher levels of this present in the bone marrow which results in lower toxicity here and less myelosuppression overall
What harmful substance is produced from the activating hydroxylation reaction of Cyclophosphamide?
Acrolein
What harmful reaction can acrolein cause?
Hemorrhagic cystitis
-toxic to bladder mucosa
What substance is administered to counteract acrolein in the bladder?
Mesna
(accumulates in the urine)
-free thiol (nucleophile) on mesna reacts with and inactivates the acrolein metabolites (electrophile)
-adding a charged group to the acrolein prevents it from going into cells
What is Mitomycin C?
Alkylating agent
(aziridine-containing natural product)
*can form bifunctional adducts (crosslinks)
What are platinum drugs?
Covalent crosslinkers that do not alkylate (do not have alkyl groups)
What is cisplatin?
Platinum drug, the original prototype
What are the resistance mechanisms to alkylators and platinum compounds?
-Increased intracellular concentration of non-protein thiols, especially glutathione
(react with electrophilic drugs)
-Increased expression of cellular glutathione S-transferase (GST)
What is the function of topoisomerases?
-Provide a mechanism to reduce localized supercoiling
-Provide access to double stranded DNA by enzymes responsible for replication, transcription, and repair
What is the function of Type 1 Topoisomerases?
Cut one strand of double stranded DNA
-relax the remaining strand and reanneal
How do Topoisomerase I inhibitors work?
Covalently bind Top1 ad blocks the re-ligation of DNA from happening
*Top 1 is not just inhibited, it is stuck onto DNA covalently
-Results in inactive Top 1, broken DNA, and a glob stuck to DNA (DNA cannot function)
Cells in what phase are most sensitive to Topo 1 cleavage?
S
What are Topotecan and Irinotecan?
Topoisomerase 1 inhibitors
-semisynthetic analogs of natural product camptothecin
Which Topoisomerase 1 inhibitor is a prodrug?
Irinotecan
Before being prescribed Irinotecan, patients must be genetically tested for what?
Low expression of UGT1A1
-this can lead to increased toxicity
What is the function of Topoisomerase II ?
Relieves torsional strain and untangles DNA
-by catalyzing double-stranded DNA breaks
How do Topoisomerase II inhibitors work?
Bind TOP after it has broken DNA and prevent the re-ligation of DNA
This causes the double-stranded breaks in the DNA to be stuck
Topoisomerase II is stuck covalently to DNA
Which topoisomerase inhibitors are considered chemotherapies?
ONLY those that produce double-stranded DNA breaks
What is Doxorubicin?
Topoisomerase 2 inhibitor
Which drug is used to prevent patients from developing cardiotoxicity associated with free radicals formed with Doxorubicin?
Dexrazoxane
What is Etoposide?
Topoisomerase 2 inhibitor
*blocks religation of double stranded breaks but does not intercalate
What is Bleomycin?
Glycopeptide antibiotic
What is dynamic instability?
Proteins build up microtubules (polymerization) until they get to a point where they just fall apart
-Growing and shrinking of microtubules happens on its own
What are the 2 requirements for the spindle assembly checkpoint?
Kinetochores need to be attached to the spindle microtubules
Needs to be kinetochore tension (need kinetochores to be attached to both sides so they can pull the sister chromatids apart)
What is a Vinca Alkaloid?
Prevent microtubule assembly
(cannot build the microtubule)
What is a Taxane?
Prevent microtubule disassembly
(stabilize the microtubule, cannot pull chromosomes apart, cannot search for chromosomes, eventually run out of tubulin monomers)
What was the first immunotherapy?
Coley’s toxin
What is the function of B cells?
Produce antibodies
If the stem of all monoclonal antibodies is -mab, what are the 4 possible substems?
-o = mouse
-xi = chimeric
-zu= humanized
-u = fully human
What was the CLEOPATRA trial?
Clinical
Evaluation
Of
Pertuzumab
And
Trastuzumab
What is the function of CD20?
-Regulates an early step in the activation of the cell cycle and differentiation
-Works with B-cell receptor to drive proliferation of B-cells
-Role in proliferation of B-cell lymphoma
-Binding to this with antibodies induces antibody-dependent cytotoxicity
What cells express CD20?
Normal B lymphocytes
Immature pre-B cells
B-cell non-Hodgkins lymphoma cells
