Interview with a scientist: drug repurposing in oncology
Drug repurposing is the strategy of using existing drugs originally developed for a specific disease to treat other diseases. We have interviewed Dr. Joanna Zawacka-Pankau about her research in drug repurposing to treat cancer.
Academia and research companies play an active role in drug discovery. De novo drug discovery is a lengthy and costly process that involves large investments by pharmaceutical industry corporations and national governments. De novo drug discovery is an inefficient process with a low rate of new therapeutic discovery.
As opposed to de novo drug discovery, the strategy of using existing drugs originally developed for a specific disease to treat other diseases has found some success across medical fields in the last decades.
This strategy called “drug repurposing” is defined as the use of already approved commercially available molecules, that have proven safe in clinical trials, for indications different from the intended original ones.
From a scientific standpoint, the most rewarding advantages of drug repurposing, among others, are the discovery of novel therapies for unmet clinical needs, and the faster access of drugs to patients.
Today we meet with Dr. Joanna Zawacka-Pankau, Ph.D. in biochemistry, active as a researcher in Stockholm and as a lecturer at Warsaw University. She has been a Principal Investigator on several research grants on pharmacological activation of p53 protein family members for improved cancer therapy, both in Poland and in Sweden.
We asked her 5 questions about her research efforts in drug repurposing in oncology.
Q1: In one or two sentences, what is the most critical question you want to address?
In my endeavors, I strive to deliver affordable and non-toxic treatment for cancer patients by applying a drug repurposing approach to re-activate p53 protein family members, i.e. the tumor suppressor proteins, p53 and p73. These proteins play an active role as a barrier against cancer through regulating the cell cycle, apoptosis, and genomic stability through several mechanisms.
Q2: What is innovative about your research?
Drug repurposing is still a neglected strategy based on using a drug already on the medical market for other indications.
In our case, we want to treat cancer with compounds already clinically used in the photodynamic therapy of actinic keratosis and age-related macular degeneration.
Pancreatic cancer, for example, remains one of the most aggressive tumors. Late diagnoses, often linked with the asymptomatic disease progression, make pancreatic cancer difficult to treat.
We have assessed drugs that are already clinically used to treat actinic keratosis and age-related macular degeneration and showed that the compounds induce apoptotic death of cancer cells.
We found that BPD (also known under commercial name verteporfin®), inhibits the proliferation of pancreatic cancer cells without affecting non-transformed cells.
The mechanism is via activation of the p73 tumor suppressor and inhibition of the oncogenic thioredoxin reductase.
This is a brilliant result!
Molecules with a complementary mechanism of action inducing cell death might be very promising candidates for improved cancer therapy in pancreatic cancer patients.
Q3: What is the most challenging part of your research?
The challenge is, for sure, the persisting rejection bias towards drug repurposing in oncology. The trend prevails despite the great success of ATRA, all-trans retinoic acid successfully repurposed to cure acute promyelocytic leukemia (APL). Also, the inaccessibility of high-affinity antibodies against p73 is halting the work with the clinical samples.
Q4: Which technology have you found useful to answer your research questions?
So far, we have applied standard biochemistry methods such as immunoprecipitation, yeast-based reporter assay, or fluorescence hybridization assay to study the protein-protein interactions in cells.
Our next step is to apply the customized proximity-ligation assay. The advantage of this technique is that it allows for the detection of protein-protein complexes in different cellular compartments and enables monitoring of how the complexes are disrupted upon drug treatment.
Next, the method is sensitive because of the signal amplification through oligo-linked antibodies and the rolling circle amplification. This is particularly important while working with isoforms which are often expressed on the low level in the tissue. Lastly, the method leaves space for further modifications, improving the signal intensity, which I find especially exciting.
Q5: If you use primary antibodies, could you explain how they have helped you or might help you with your research scope?
Primary antibodies are a fundamental part of our research. We have used antibodies against p53, p73, PUMA, p21, MDM2, and others. We are now looking for antibodies against different isoforms of p73.
Antibodies against different isoforms of p73, currently not commercially available, might be helpful not only in the context of the extended target validation studies but also in better understanding the biology of p73 protein.
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- L Jiang, J Zawacka-Pankau The p53/MDM2/MDMX-targeted therapies-a clinical synopsis. (2020) Cell Death & Disease 11 (4), 1-4
- A Sznarkowska, A Kostecka, A Kawiak, P Acedo, M Lion, A Inga, and J Zawacka-Pankau. Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells. (2019) Cell Division 13: 10.
- L Jiang, N Malik, P Acedo, J Zawacka-Pankau Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukemia cells. (2019) Cell death discovery 5 (1), 1-11