Research Investigations
While chemotherapy drugs are highly effective in combating the growth of
tumours, resistance to these drugs typically develops during treatment,
resulting in treatment failure and progression of disease. Patients then
move on to other chemotherapy drugs but these drugs often also become
ineffective in halting tumour growth. This phenomenon is called “multidrug
resistance”. The research efforts of my research group are focused on
better understanding factors that affect the response of tumours to
chemotherapy drugs and how tumour cells develop resistance to
chemotherapy.
Reduction in Tumour RNA Quality and Response to Chemotherapy in
Breast Cancer Patients
Actively growing tumour cells produce large quantities of a large molecule called
ribonucleic acid (RNA). We have observed in a national clinical trial (NCIC-CTGMA.22) that the quality (integrity) of RNA in tumours falls dramatically in about
half of breast cancer patients in response to chemotherapy. Another clinical trial
in the United Kingdom has recently reproduced these findings. In the MA.22
study, we observed that this drop in quality was highest for the highest doses of
chemotherapy drugs. Moreover, low tumour RNA quality mid-treatment predicted
complete destruction of the tumour after chemotherapy. In contrast, little change
in RNA quality was observed in blood cells from the same patients at any point
during treatment.
Our findings suggest that a patient’s response to
chemotherapy may be effectively measured by monitoring RNA quality early in
treatment (after 1-3 cycles). Patients exhibiting reductions in tumour RNA quality
would be assured that they are responding to chemotherapy, while patients with
high tumour RNA quality after 1-3 cycles could be switched quickly to alternate
treatments, such as surgery, radiation therapy, or other drugs. This will be
assessed in upcoming clinical trials in collaboration with the Ontario Clinical
Oncology Group, Sunnybrook Hospital, McMaster University, the University of
Waterloo, and the London Regional Health Sciences Centre.
Role of Aldoketoreductases in Resistance to the Anthracycline Class of
Chemotherapy Drugs
We have recently observed that breast tumour cells that have acquired
resistance to a class of chemotherapy drugs called anthracyclines have high
levels of protein molecules called aldo keto-reductases (AKRs). The AKRs play a
natural role in breast cells, where they stimulate estrogen production. Estrogen,
in turn, stimulates rapid growth of breast tumour cells, making them very
sensitive to anthracyclines. To counteract this, we observed that anthracyclineresistant cells produce very little of the receptor for estrogen. The cells thus grow
more slowly and are not killed effectively by chemotherapy drugs. In addition,
the AKRs have the ability to alter the structure of anthracyclines, converting the
drug to a form that can no longer reach its target in tumour cells (DNA within the
nucleus). In fact, the drug appears to be sequestered in the lysosomes of cells
away from the nucleus. Consequently, the altered drug is almost completely
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Parissenti – Research Investigations
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Research Investigations
ineffective in killing breast tumour cells. It is also highly toxic to the heart. We
have also shown recently that other drugs that inhibit the function of AKRs can
prevent this change in anthraycline structure, restoring the ability of this class of
drugs to kill tumour cells. In the future we plan to assess whether AKR-inhibitory
drugs may improve the ability of anthracyclines to kill tumours in mice, while
reducing damage to the heart.
Tumour Necrosis Factor Alpha and Response to the Taxane Class of
Chemotherapy Drugs
Drugs such as paclitaxel and docetaxel (taxanes) are widely used in the
treatment of a variety of human cancers, including breast and ovarian cancer.
These drugs are known to bind to structures in normal and cancer cells called
microtubules that play a role in separation of chromosomes between mother and
daughter cells. This binding of the drug to microtubules prevents cell
reproduction from taking place, particularly in rapidly proliferating cells such as
tumour cells. This is thought to be the primary mechanism of action for taxanes.
We have recently discovered that taxanes also promote in tumour cells a
dramatic increase in the production and secretion of a death-inducing molecule
called tumour necrosis factor alpha (TNFa). This may be a previously unknown
mechanism by which taxanes kill tumour cells. Oddly, we have observed that
breast tumour cells resistant to taxanes have even higher levels of TNFa. While
this initially was puzzling, we also discovered that taxane-resistant cells are
resistant to TNFa-induced killing because they have lost the receptor to which
TNFa binds (TNFR1) in order to induce cell killing. In contrast, they have another
receptor (TNFR2) to which TNFa can bind, which promotes tumour cell survival.
Based on these novel findings, we now believe that TNFa plays an important role
in tumour response and resistance to taxanes. We hope to be able to block this
resistance mechanism in the future, in order to improve the effectiveness of
taxane chemotherapy.
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