Pharm: Targeted Therapies Flashcards
The most common inherited breast cancer TSG mutation is what?
BRCA 1/2
One cancer accelerated by a mutated c-kit oncogene is the ____ ____ tumor.
GI stromal tumor
Mutations in ____ and ____ can lead to malignancies in a small percentage of lung cancers.
EGFR; ALK
Usually, how many mutations are required to allow cells to overcome the body’s boundaries for cell growth?
multiple.
What is the goal of genomic medicine in cancer therapy?
to identify mutations sites and treat specifically the problem with targeted therapy
____ receptors are very important targets for patients with breast and prostate cancers.
Hormone
What is c-Kit?
an oncogene that encodes a cell surface RTK that can activate the RAS and the PI3K pathways
What type of cancer is c-Kit mutation associated with?
GI stromal tumor (GIST)
What drug works well against c-Kit mutation tumors?
imatinib - because it turns off the tyrosine kinase, which mutated c-Kit is
Adenocarcinoma of the lung often arises in non-smokers, especially in ____ countries.
East Asian
Cetuximab blocks what receptor, and what cancer does this treat best?
EGFR (blocks externally); colon cancer
Genes with mutations that are most amenable to treatment with drugs that inhibit EGFR are located where?
exxons 19 & 21 of the EGFR gene
Erlotinib blocks what receptor, and what cancer does this treat best?
EGFR kinase (blocks internally); lung cancer
An adenocarcinoma of the lung is found to have an ALK mutation. What drug will be therapeutic for this cancer?
Crizotinib
What is the most common cause of tonsillar cancer in non-smokers?
HPV infection - common cause of oropharyngeal cancer
In head and neck cancer due to EGFR mutation, EGFR can be inhibited by the drug ____, which inhibits the receptor from the ____ side.
Cetuximab; externally
4 goals of treatment, according to Dr. Weir:
- cure disease
- extend life
- better quality of life
- prevent impending disaster
What is the most common brain neoplasm and from what cells does it derive?
Glioma; glial cells
What is the grading scale for glioma severity?
Grades 1-2 considered benign; Grades 3-4 considered malignant; Grade 4 is a glioblastoma
A recurrent glioblastoma would most likely respond to targeted therapy with what drug?
bevacizumab
Bevacizumab is useful therapy for what type of cancer?
glioblastoma - VEGF inhibition
Cetuximab is useful therapy for what type of cancer?
colon cancer, H&N cancer, lung cancer - EGFR inhibition
Crizotinib is useful therapy for what type of cancer?
lung cancer - EML4-ALK inhibition
Erlotinib is useful therapy for what type of cancer?
lung cancer - good for EGFR mutation in adenocarcinoma
Imatinib is useful therapy for what type of cancer?
CML - BCR-ABL mutation
GIST - c-Kit mutation
Glioblastomas produce a lot of ____ for promoting angiogenesis.
VEGF
What is the MOA of bevacizumab?
binds VEGF-A and prevents it from binding the VEGF-2 receptor; thereby preventing the Ras and PI3K pathways
What does bevacizumab achieve clinically?
takes away the glioma side effects by taking away the blood supply and reduces the swelling that’s putting pressure on other brain areas and producing symptoms
What is a common cause of iron deficiency anemia, and how could it also be due to cancer?
to lose iron is to lose blood! so a common cause is GI tract bleeding; could also be renal cancer causing blood to be lost slowly in urine
Renal cell carcinoma and glioblastomas are particularly dependent on ____, providing a target for anti-cancer therapy.
angiogenesis
Von Hippel Lindau syndrome comes from a mutation in ____ (gene) which encodes ____ (protein).
TSG; hypoxia inducible factor (HIF)
Most clear cell carcinomas of the kidney have a mutation in what gene?
von Hippel Lindau
Mutation of von Hippel Lindau results in lost inhibition of ____, which drives production of what and results in what?
HIF, which drives production of VEGF which stimulates angiogenesis allowing for tumor growth and expansion
What is the MOA of sunitinib, and what cancers is it good at treating?
inhibits angiogenesis by blocking VEGFR tyrosine kinase activity intracellularly, and preventing the RAS and PI3K pathways from inducing angiogenesis; makes it good at treating renal cancer
Breast cancers that are both estrogen and progesterone receptor positive means what?
it means that the cancer is in part driven by estrogen and progesterone
Where is the estrogen receptor located?
intracellularly; it’s a hormone receptor
True or false: there is cross-talk between the estrogen/estrogen receptor and the GFR/mTOR pathway.
True
What is the MOA of tamoxifen and what cancer is it best at treating?
blocks estrogen receptors and hormone response of breast cancers
What is another good drug for treating estrogen receptor-positive breast cancers and in what population is this drug useful (and why)?
aromatase inhibitors–block formation of estrogen; only useful in post-menopausal women because estrogen production will be increased to overcome the inhibition
What drug is used to block mTOR? Blocking mTOR in addition to estrogen receptors will have what effect on breast cancer?
Everolimus; together with estrogen receptor inhibitor (tamoxifen) it will decrease the time to cancer progression
What is the HER receptor family?
TM receptor tyrosine kinase that binds GFs, implicated in breast cancers
What is the MOA of Trastuzumab and what cancer does it work best on?
externally blocks HER-2 receptor; works best on breast cancer recurrence and metastasis
What other drugs combine well with Trastuzumab?
hertuzimab - another HER inhibitor; also combines with DM-1 a chemotherapy that is only brought into a breast cancer cell
What drug would prostate cancer respond best to?
enzalutamide
How does testosterone interact with the androgen receptor?
testosterone enters the cell, is converted to DHT; DHT binds the cytoplasmic androgen receptor and associates with AR; then transmigrates to nucleus to transcribe genes
What does the LHRH agonist and antagonist do?
blocks testosterone production; but the agonist will first release a lot of LHRH, so requires simultaneous androgen receptor inhibition
What is the MOA of enzalutamide and what cancer does it best treat?
it binds and blocks androgen receptor, prevents its migration into the nucleus, and blocks action within the nucleus; treats prostate cancer
What does castrate resistant prostate cancer mean?
it means it is progressing despite markedly reduced testosterone levels
What cancer is the B-Raf mutation associated with?
melanoma
Melanoma that develops from sunburn in youth is associated with mutation in what gene?
B-Raf V600
What pathway is B-Raf involved in?
B-Raf –> Mek –> ERK –| BIM –> Bcl-2/XL –> survival
*So if B-Raf is mutated and fails to produced ERK, BIM won’t be inhibited and the cell will survive
What pathway is PTEN involved in?
PTEN –| PI3K –> AKT –> BAD –| BAD/BAX –> BCL-2/XL –> survival
*So if PTEN is mutated and fails to inhibit PI3K, BAD won’t be inhibited and the cell will survive
What is the MOA of vemurafenib and what cancer is it good at treating?
inhibits the mutated BRAF V600E/K, preventing cancer cell survival; good for melanoma
A germline mutation in PTCH will lead to what syndrome, which is a condition involving defects of multiple body systems and a predisposition to what carcinomas?
Gorlin syndrome; basal cell carcinomas
What is the MOA of vismodegib and what cancer is it useful in?
blocks SMO in the the Hedgehog pathway therby preventing tumors; useful in basal cell carcinoma
