Question

She (Patricia Keely, 1963-2017 )was a 21-year-old undergraduate at the University of Minnesota when she discovered a lump near her neck. It was Hodgkin's lymphoma, a cancer of the lymphatic system. She underwent radiation therapy and later also chemotherapy.

Despite a cancer recurrence in grad school, she earned a doctorate in cell biology from Minnesota and embarked on the research career that brought her to Madison after stints at Washington University in St. Louis and the University of North Carolina.

Doctors aren't sure what causes Hodgkin's lymphoma. But it begins when an infection-fighting cell called a lymphocyte develops a genetic mutation.

Prior infection with Epstein-Barr virus is associated with increased risk of getting cancer later on.


The mutated cells to multiply rapidly, causing a large number of oversized, abnormal lymphocytes to accumulate in the lymphatic system, where they crowd out healthy cells and cause the signs and symptoms of Hodgkin's lymphoma.

Symptoms are vague:
•Painless swelling of lymph nodes in your neck, armpits or groin
•Persistent fatigue
•Fever
•Night sweats
•Unexplained weight loss
•Severe itching

The main treatments for Hodgkin lymphoma are chemotherapy alone, or chemotherapy followed by radiotherapy.

Dr. Patricia Keely first became a group leader at the University of Wisconsin-Madison and later became the Chair of the Department of Cell and Developmental Biology. She studied the mechanisms driving breast cancer development and metastasis. She was particularly interested in how the microenvironment in the vicinity of tumor cells influences cancer development

In 2006, Dr. Patricia Keely was diagnosed with esophageal cancer, probably caused by the radiation that cured her lymphoma. She underwent surgery in January 2006. Doctors removed two-thirds of her esophagus and the top of her stomach.
After surgery, "my prognosis for being without disease was only 50-50," Dr. Keely said. If the cancer came back, it would mean it has spread and there would be no cure.

She got different opinions from doctors. She was told that chemotherapy would be effective only if accompanied by radiation, but she could not have any more radiation therapy because of her earlier treatment.

She plunged into medical literature and found a clinical trial at the Mayo Clinic for an experimental drug called Iressa intended to prevent a recurrence of esophageal cancer.

"I understand the mechanism" of the drug, she said. "It made intellectual sense to me. It blocks a signaling pathway that is found to be increased in metastatic esophageal cancer."
Question 1:
Dr. Keely chose to enter a clinical trial where cancer patients were treated with IRESSA. IRESSA is a targeted EGF receptor drug. What type of mutation involving the EGFR might thus have been present in Dr. Keely’s metastatic tumor? List 2 possible oncogenic EGFR alterations.





Question 2:
How does the EGF receptor inhibitor IRESSA act (What domain in EGFR does IRESSA target?). What alternative anti-EGFR drugs would be available that would act differently than chemical inhibitors?






Question 3:
How might IRESSA have helped Dr. Keely to increase her survival chances once diagnosed with esophageal cancer? What would IRESSA do in terms of pathway effect and cellular processes affected?







Question 4:
IRESSA needs to be taken continuously by patients undergoing treatment. Often, tumor cells develop resistance after a while. What type of resistance mutants are frequently observed in the EGF receptor?












Question 5:
IRESSA (Geftinib) is one approved drug that targets the EGFR. Tarzeva (Erlotinib) and Gilotriv (Afatinib) are others. Are these targeting the same EGFRs? How about their mechanism? And what about Erbitux (Cetuximab)?









Question 6. Particular receptor tyrosine kinases (RTKs) that promote excessive cell division are found at high levels on various cancer cells. A protein called Her2 is a version of EGFR involved in tumor development. Choose the best statement about Her2 action.

A. Activation of Her2 causes cells to undergo apoptosis.
B. Activation of Her2 promotes progression through the cell cycle.
C. Activation of Her2 has no effect on the cell cycle.
D. Activation of Her2 causes cells to enter the G0 (quiescent) phase of the cell cycle.
E. All of the above



Question 7. Knowing how receptor tyrosine kinase signaling through the EGF type family of receptors works, what additional pathway molecule would you target for effective anti-cancer therapy to eliminate cancer cells that acquired resistance to IRESSA? Choose the most effective way to target.

A. Drugs that inhibit Raf kinase
B. Agents that inhibit EGFR activation, such as the monoclonal antibody drug herceptin
C. Drugs that inhibit mTOR
D. Drugs that inhibit Ral-GDS
E. Drugs that inhibit both, Raf and PI 3-kinase activity

Why do you think this is the most promising approach? Explain inn 1-2 sentences

answer only first 3 questions please according to the text

Answer 1

1) Possible oncigenic EGFR alterations are:

- Amplification and point mutations at the genomic locus

- Transcriptional upregulation or ligand overproduction due to autocrine/paracrine.

2) Gefitinib is the first slective inhibitor of EGFR .

Available EGFR drugs that act differently than chemical inhibitors:

-Tryosine kinase inhibitors(TKIs)

-erlotinib

-gefitinib

-lapatinib

3) IRESSA inhibits the tryosine kinase activity of the epidermal growth factor by blocking the ATP binfing site.

4) Somatic mutations of the HER2 gene were identified in a very small fraction of lung adenocarcinomas. HER2 mutations are mostly found in females, non smokers and adenocarcinoma patients.

However the mutations of HER2 are mutually exclusive with those of EGFR in the tumor cells.Most tyoes of HER2 mutations are in-frame insertion mutations in exon20.

5) Both Erlotinib amd Afatinib target RNR and EGFR resulting in down regulated protein levels in lung cancer as well as in non-cancer cells.

Erbitux(Cetuximab): It binds to the EGFR on both normal and tumor cells. Cetuximab competitively inhibits the binding of EGF and TGF alpha. Thereby reducing their effects on cell growth and metastatic spread.

6) option D