While the study of targeted therapies in cancer is a well-established field, it remains an area of incredible promise with ample room for further discoveries. A 10-year collaboration between scientists at The Wistar Institute and the University of Pennsylvania has recently resulted in the emergence of an exciting new target for cancer therapy, heat shock protein 70 (HSP70), that we believe could be very helpful in treating patients with melanoma.
HSP70 is a protein that is expressed at extremely low levels in normal, unstressed cells. However, when cells are exposed to various forms of stress, such as heat shock, oxidative stress, altered pH, heavy metals, or hypoxia, this protein becomes massively upregulated and expressed at levels hundreds of times higher than what we observe in normal cells. These various forms of stress cause proteins to become misfolded, and once these misfolded proteins accumulate, they become toxic to the cell. HSP70 functions to unfold these misfolded proteins and allow them to refold, thereby promoting cell survival.
In the laboratory of Maureen Murphy, PhD, we began our collaboration with the lab of Donna L. George, PhD, at the University of Pennsylvania to determine the role of HSP70. As one can imagine, tumor cells routinely find themselves exposed to enormous levels of stress. When we compared melanoma tumor cells with those of normal skin cells, we found that the melanoma cells expressed markedly higher levels of HSP70 (Figure)
Figure. Expression of HSP70 Is Higher in Cancer Than Normal Skin
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In a fitting example of how Wistar researchers work together across disciplines and programs to arrive at the best answers to pressing scientific questions, we then collaborated with the Wistar Institute’s Melanoma Research Center to better understand the relationship between HSP70 and melanoma tumor cells. Along with Julie I-Ju Leu, PhD, an assistant professor of Genetics at Penn, I helped determine whether a novel inhibitor of HSP70, PET-16, could be used to treat melanomas. We found that PET-16, which Leu and George first identified, was toxic to melanomas but managed to spare normal melanocytes. Using mouse models, we were able to show that PET-16 could effectively eradicate melanoma tumors grown in mice without causing any toxicity to the mice.
Additional research led Leu to explain why PET-16 was only toxic to cancer cells. PET-16 was able to selectively kill tumor cells and spare normal cells not simply because of the low levels of HSP70 in normal cells. Rather, she discovered that the HSP70 protein in tumor cells was inherently different from HSP70 in normal cells, causing it to bind hundreds of times better to PET-16, com- pared with normal cells. This research suggests than an altered conformation of HSP70 exists in tumor cells, making the form of this protein present in tumor cells particularly sensitive to PET-16.
This is particularly exciting for us because this is the very definition of targeted therapy. Normal cells do not require HSP70 to survive, and the HSP70 that is found at low levels in normal cells is different from the HSP70 in cancerous cells, making it an ideal therapeutic target.Commercial Development Advances
The development of HSP70 inhibitors for cancer therapy has received limited attention to date, in large part because pharmaceutical companies have invested significant effort targeting another heat shock protein, HSP90. Despite some promising results in clinical trials, HSP90 inhibitors are limited in their efficacy because treatment of tumor cells with HSP90 inhibitors leads to a significant compensatory upregulation of HSP70, which promotes survival. Now pharmaceutical companies are focusing their attention on HSP70, with the promise of combining HSP90 and HSP70 inhibitors, as a “one-two” punch for cancer therapy.
Our research progress has been validated and our efforts rewarded with an inclusion in a team grant at The Wistar Institute funding research into the use of HSP70 inhibitors to eradicate melanoma.
We also recently received a 2014 Discovery Fast Track Challenge award from GlaxoSmithKline (GSK), one of only 15 projects selected worldwide for the program. Through the program, GSK partners with academic institutions in order to facilitate the tran- sition of promising lead compounds from preclinical studies toward clinical trials in human patients.
This partnership between academia and a pharma- ceutical company like GSK is very helpful because we believe we have a very promising target not just for melanoma but also for a number of other types of cancer. Since GSK has a plethora of exploratory compounds, the collaboration exponentially increases our chances of finding a viable drug candidate for our target and of doing so much more quickly.