Lec 7 & 8 - Cancer Pharmacogenomics 1

Question 1

CPIC?

Answer 1

clinical pharmacogenetics implementation consortium
↳ everything on pharmacogenomic

Question 2

For most of PGx look at GENETIC VARIATIONS
(differences in DNA sequence observed in the population)…List of things that can occur in the cell that can lead to mutation??? Define mutation???

Answer 2

Question 3

CANCER PGx BASICS (know general)

Answer 3

• Cancer is a group of disorders characterized by uncontrolled cell growth…. Multiple stages are involved in the development of cancer.
• Cancer may involve inherited susceptibility factors as with PGx of other diseases.
• However, somatic mutations acquired in the development and progression of cancer are key considerations in cancer PGx, distinguishing cancer PGx from other areas of PGx.
• Genomic studies may assist in predicting who will develop cancer, which aids in the development of cancer chemoprevention strategies as well as provides information on the most appropriate therapeutic regimens for cancer treatment.
• Cancer PGx may involve pharmacokinetic, pharmacodynamic, as well as other treatment considerations.
• Each individual cancer and cancer type has genetic characteristics that may be targeted for therapy, which is facilitated by PGx.

Question 4

Cancer – Somatic Mutations

Answer 4

Question 5

Distribution of Genetic Aberrations in AML
…talk about the translocation

Answer 5

Question 6

Example of Cell Signal Transduction and normal cell proliferation

Answer 6

Question 7

Oncogenes are Mutant Forms of Proto-Oncogenes (abnormal cell proliferation)… leading into MaB and Kras mutation???

Answer 7

Question 8

EGFR Inhibitors & Mutant KRAS… Examples of monoclonal antibodies currently approved to
treat metastatic colorectal cancer (mCRC)…and talk about KRAS protein!

Answer 8

Examples of monoclonal antibodies currently approved to treat metastatic colorectal cancer (mCRC):
* Cetuximab
* Panitumumab
.
MOA: Bind to extracellular EGFR domain leading to inhibition of downstream signaling
-Only 10-20% of patients with mCRC benefit from anti-EGFR therapy
- EGFR expression does not correlate with clinical benefit

Question 9

KRAS mutations in cancer. Functional effect… and evidence/ studies

Answer 9

• Functional effect: Activating mutations in
  KRAS result in activation of downstream
  signaling pathways and confers resistance to
  inhibition of cell surface receptor tyrosine
  kinases such as EGFR (eg. mab that acts on surface of cell is useless!)
• Prevalence: The prevalence of mutated
  KRAS ranges between 27- 43% in tumor
  samples collected from colorectal cancer
  patients across 7 trials

Question 10

Ras Inhibitors – Sotorasib (LUMAKRAS®) inhibits Ras (Kras) harboring a G12C mutation…

Answer 10

Question 11

What’s kinases? What’s Epidermal Growth Factor Receptor (EGFR)?

Answer 11

• Kinases – targets of kinase inhibitors
• Kinase – an enzyme that catalyzes the transfer of a phosphate from a high energy phosphate-donating molecule to a hydroxyl group on an amino acid (e.g., tyrosine, serine, or threonine) of a protein substrate
• When a kinase phosphorylates a protein, the activity of the protein is changed and becomes more active.
  -This often results in altered activity of the protein substrate as part of a biochemical pathway that may result in increased cellular proliferation or survival
  – often involved in the activity of oncogenes (gain of function)

Question 12

EGFR Small Molecule Inhibitors
…know the name and structure of the prototype!

Answer 12

Question 13

BRAF Inhibitors

Answer 13

• Dabrafenib (Tafinlar®) and
  Vemurafenib (Zelboraf®) are
  BRAF inhibitors used in the
  treatment of melanoma. The
  name “vemurafenib” comes
  from V600E mutated BRAF
  inhibition.
  .
  NOTE: There is also a C-RAF but it is different than B-RAF! B-RAF is the one that is commonly mutated in melanoma

Question 14

MEK Inhibitors

Answer 14

Cobimetinib (Cotellic®) and
Trametinib (Mekinist®) are
MEK 1 & 2 inhibitors used in
the treatment of melanoma.
.
not used commonly… doesn’t work as well and have many have SE.

Question 15

Germline variations and drugs correlating with it that we will be talking about going forward. List them!

Answer 15

1.) Thiopurines (GMP, 6TG, aza) and TPMT ( 2/3C/3A - decreased ability)
2.) Irinotecan and UGT1A1(28 - decreased ability)
3.) Tamoxifen and CYP2D6 (many)
4.) Rasburicase and G6PD deficiency (A variant / Mediterranean)
5.) Flurorpyrimidines and DPYD deficiency

Question 16

Thiopurines (e.g., 6-Mercaptopurine) & Thiopurine S-methyltransferase (TPMT) - (TPMT2, TPMT3A, TPMT*3C)

Answer 16

This enzyme TPMT inactivates thiopurines. The variants of TPMT like TPMT2, TPMT3A, TPMT*3C causes a reduction of activity! so lets say if someone has the alleles 3/3… they have very reduced activity of TPMT so you need to reduce medication dose or else they can OD/ have toxicity!

Question 17

Thiopurines (e.g., 6-Mercaptopurine) & Thiopurine S-methyltransferase (TPMT) - (TPMT2, TPMT3A, TPMT*3C)…clinical application and clinical relevance

Answer 17

Question 18

Irinotecan (Camptosar) and UGT1A1/ the important variant

Answer 18

• Camptothecin class of topoisomerase inhibitors: Binds to topoisomerase I and inhibits the cleavable complex
  resulting in ds DNA breaks
• Irinotecan is a prodrug that is metabolized to SN-38, the
  active form of the drug… Metabo by UGT1A1
• Significant side effects including diarrhea, neutropenia, and vascular syndromes
  .
• Gene/Allele of interest: UGT1A1*28
• Result of 7 TA repeats in the promoter region instead of 6 repeats–> ~ 40% reduced expression
• Functional effect: reduced UGT1A1 transcription & enzyme (or glucuronidation) activity
• Associated with reduced clearance of SN-38 (active and toxic metabolite)
• Associated with mild unconjugated hyper-bilirubinemia
  (Gilbert’s Syndrome) AKA jaundice
  .
  NOTE: UGT1A128 variant causes a reduced in activity …thus you cannot clear drug fast enough leading toxicity…so if someone have a UGT1A128 variant.. you would need to reduced the dose.

Question 19

Tamoxifen & CYP2D6 Variants

Answer 19

Question 20

Tamoxifen Biotransformation

Answer 20

Question 21

Rasburicase & G6PD Deficiency . . . talk about the function of Rasburicase

Answer 21

• Rasburicase (Elitek®): Used to clear uric acid from the blood for the prevention and treatment of tumor lysis syndrome in people receiving chemotherapy for hematologic cancers such as leukemia and lymphoma.
• In humans, uric acid is the final step in the catabolic pathway of purines.
• Rasburicase catalyzes enzymatic oxidation of poorly soluble uric acid into an inactive and more soluble metabolite allantoin with carbon dioxide and hydrogen peroxide as byproducts in the chemical reaction.
  .
  NOTE: Rasburicase metabolizes uric acid! Remember if patient have tumor lysis syndrome? there’s a lot of DNA getting into the system and DNA is broken down and purine is being broken down to uric acid issue? …you can give allopurinol but you had to get rid of uric acid so you may use Rasburicase … however it does give oxidative byproducts.. can cause issue in ppl w/ G6PD Deficiency

Question 22

G6PD Deficiency and the issues when giving Rasburicase

Answer 22

• Gene/Allele: Glucose-6-phosphate dehydrogenase
  (G6PD) A-variant and Mediterranean variant
• Functional Effect: Excessive hydrogen peroxide is
  produced as rasburicase converts uric acid to more
  soluble allantoin
• Excess hydrogen peroxide places patient with G6PD
  deficiency at risk for hemolytic anemia and methemoglobinemia
• (The Pathology): People with G6PD deficiency are
  at risk of hemolytic anemia in conditions of oxidative stress. States of oxidative stress can result from infection, medications*, and certain foods.

Question 23

Fluoropyrimidines: Capecitabine, 5-Fluorouracil,
& Dihydropyrimidine Dehydrogenase (DPYD) Deficiency

Answer 23

DPYD - The protein encoded by this gene is a
pyrimidine catabolic enzyme and the initial and ratelimiting factor in the pathway of uracil and thymine
catabolism. Mutations in this gene result in
dihydropyrimidine dehydro-genase deficiency, an
error in pyrimidine metabolism associated with
thymine-uraciluria and an increased risk of toxicity
in cancer patients receiving 5-fluorouracil
chemotherapy. (PubMed)