Download The mechanism of cell proliferation

November, 2005
The mechanism of cell proliferation
Prof. Ronit Sagi-Eisenberg
[email protected]
The following case report is aimed at assisting you in a self teach study on the
topic of Cell Proliferation. The ultimate goal of this study is to get acquainted with
and fully understand the molecular mechanisms of cell proliferation and their
clinical implications, namely the molecular bases of malignancy.
Towards this end please read carefully the following case report and use the questions
that follow as direction points.
A.- a breast cancer patient
A. is 40 years old female, married for 19 years, with no children. During a routine
self exam of her breast, A. found a lump and a week later had a mammogram.
Looking at the film, the doctor immediately referred A. to a surgeon. The surgeon told
her he was certain it was breast cancer. On the next day, A. had a formal biopsy at the
Hospital. This was a 30-minute procedure after which A. returned home.
Unfortunately, the results of this needle aspiration were non-conclusive for cancer. A.
was quite happy about it but the doctor warned her not to get her hopes up because
this happens sometimes with the Fine-needle aspiration (FNA) and he still felt it is
cancer. Two days later A. had a core biopsy of the lump. The doctor told her she
would get the pathologist’s report on the following day.
Upon her next appointment with her doctor, he told her that the pathologist’s report
confirmed it was breast cancer and some of the lymph nodes also had some evidence
of cancer. A. then had a modified radical mastectomy and removal of some lymph
nodes on the next day. The doctor also explained to A. that the pathology report
includes information regarding how aggressive the cancer cells are, how quickly they
divide and how receptive they are to certain drug treatments. He also mentioned the
fact that he is awaiting the evaluation of her HER2 status.
Based on the pathological evaluation, A.’s cancer was staged as grade 3, stage IIB and
HER2-positive (+3) but estrogen receptor negative. The doctor said that this means
that A. will have to have both radiation and chemo treatments for the next six months.
He also said that being HER2-positive makes her a good candidate for Herceptin
treatment. He explained that Herceptin is a monoclonal antibody engineered through
Molecular Biology and produced to provide specific anti-tumor action within the
human body. The doctor also mentioned the novel drug IRESSA alone or in
combination with other drugs such as docetaxel and other pipeline drugs such as
R115777.
A. began treatment with four courses of doxorubicin IV and cyclophosphamide IV -one course every three weeks. Three weeks after the fourth course she began four
courses of taxol and Herceptin followed by 28 treatments of radiation therapy.
A. is doing well.
Guide line Questions:
1.
2.
3.
4.
5.
6.
7.
8.
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10.
11.
12.
What is HER2, how else is it known and to what family of proteins does it
belong?
Why was A.’s doctor awaiting the evaluation of her HER2 status?
What is the relationship between “HER2 status” and the aggressiveness
and therefore prognosis of the malignancy.
What is Herceptin?
Why does the finding that A. is HER2-positive make her a good candidate
for Herceptin treatment.
What is the mechanism of action of Herceptin and how is it related to the
process of receptor mediated endocytosis?
What is IRESSA (ZD-1839) and why might this drug be considered as an
option for treating A.?
What are the fundamental differences in the mode of action of Herceptin
vs. IRESSA?
The doctor also mentioned docetaxel. What is the rationale behind the use
of this drug as an anti cancer drug? What is the major difference between
this drug and drugs such as Herceptin or IRESSA?
R115777 is currently under clinical development. What is the molecular
target of this drug and what is the rationale behind its development?
A.’s treatments began with several courses of doxorubicin. What is this
drug and at which step does it act?
Categorize, according to your own perspective, all the anti cancer drugs
and treatments, which are mentioned in this case report, into groups. How
many groups do you have? What were your categories for classification?
What drug belongs to which group? Consider their mechanism of action.
PART B
General Aims:
1.
2.
3.
4.
5.
6.
7.
8.
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11.
To understand the concept of growth factor and growth factor receptor.
To familiarize yourself with the family of receptor tyrosine kinases
(RTKs).
To understand how receptor tyrosine kinases are activated.
To understand how a signal that is transmitted by an RTK is
propagated inside the cell towards the nucleus.
To understand the role and function of an SH2 domain.
To understand the molecular basis of Ras signaling.
To understand the connection between the signaling of the growth
factor receptor and the control of the cell cycle.
To understand what kind of molecules could be considered protooncogenes and how can they become oncogenes.
To understand why an oncogene causes malignancy.
To understand the importance of identification of oncogene(s)
expressed in tumor tissue in the choice of treatment.
To understand the relationship between the new generation of
signaling anti cancer drugs and oncogenes.