At the American Association for Cancer Research (AACR) Second Frontiers in Basic Cancer Research Conference this week, two interesting presentations on pancreatic cancer caught my eye. It has long been my belief that we will see no major breakthroughs for this devastating disease until our understanding of the biology advances.
Here’s a quick snapshot of each one:
EGFR Essential for the Development of Pancreatic Cancer
Barbara M. Gruener, a researcher at the Technical University in Munich, Germany stated that,1
“Originally, we wanted to characterize the known role of EGFR in pancreatic cancer to a higher extent so that EGFR targeted therapy could be more individualized.”
However, sometimes serendipity intervenes and some useful, unexpected, nuggets are revealed. In this case, she presented compelling evidence that demonstrated that:
- Despite KRAS, lack of EGFR blocks pancreatic cancer development
- EGFR plays an “unappreciated” central role early in the carcinogenic process
Now, while we know the mutation of the KRAS gene is an important factor in the development of many cancers, including pancreatic cancer, Gruener’s results suggests that despite the presence of KRAS, the development of preneoplastic precursor lesions and pancreatic ductal adenocarcinoma is blocked without the EGF receptor:
“EGFR seems to be involved in the early transdifferentiation processes of the pancreas in vivo and in vitro.”
What does this research mean in practice?
Firstly, these results were a surprise:
“With oncogenic active KRAS, you would expect that the lack of a receptor that is upstream of the KRAS signaling pathway does not impair the carcinogenic effects of KRAS almost completely.”
To me, the data strongly suggests that EGFR therapy might be a logical approach for early pancreatic cancer treatment than is currently undertaken, i.e. for advanced metastatic disease, when the tumor burden is much higher. Obviously, some clinical data will be needed to support and validate the preclinical findings, but this at least offers some pointers where we might start.
Virus Shows Promise for Imaging and Treating Pancreatic Cancer
The second abstract that really appealed to me was from Dana Haddad (MSKCC), who talked about the potential for an oncoloytic virus in pancreatic cancer 2
I confess that my first reaction was a little sceptical, as vaccines and viruses have yet to show dramatic activity in solid tumours, never mind a difficult to treat one such as pancreatic cancer. That said, let’s take a look at Dr Haddad’s research in detail.
First of all, she specified what an oncolytic virus actually is and what it does:
“Defined as viruses that selectively replicate in cancer cells with consequent direct destruction via cell lysis.
Leaves non-cancerous tissue unharmed.”
So a targeted approach, rather than a broad non-specific effect (I’m warming up already!)
One of the challenges though, is that biopsy is currently the gold standard for monitoring viral therapy in clinical trials, but these repeated biopsies are invasive and often difficult. There is therefore a need for new and improved methods for:
- non-invasive monitoring
- real time assessment of response to therapy
- monitoring of potential viral toxicity
Haddad et al., looked at the feasibility of systemic virotherapy, together with monitoring radiotherapeutic response of pancreatic cancer xenografts treated with a vaccinia virus encoding the human sodium iodide symporter (hNIS), GLV-1h153.
hNIS is a cell surface protein that mediates transport of iodine mainly in thyroid gland. The value of this approach is that it has:
- imaging potential by using several carrier free radionuclide probes
- therapeutic potential by combining radioiodine with viral therapy
GLV-1h153 was injected systemically or intratumorally into pancreatic cancer xenografts in nude mice and 124I-positron emissions tomography (PET) was used image tumors.
The results clearly showed that:
- PET signal intensity correlated with antitumor response
- Colonization of tumors with GLV-1h153 facilitated uptake of radioiodine at potentially therapeutic doses
- Combining GLV-1h153 with 131I led to enhanced tumor kill compared to either treatment alone
What do these findings mean in practice?
Dr Haddad summarized this nicely:
“It has been shown, for the first time, that vaccinia virus construct GLV-1h153 facilitates:
non-invasive long-term deep tissue monitoring of viral therapy, monitoring of tumor therapeutic response,
potential for targeted radiotherapy.”
She also went on to suggest that:
“GLV-1h153 can be directly translated to human clinical trials:
parent virus already in phase I clinical trials,
radiotracers and imaging modalities FDA approved.”
I think that we will see more clinical research evolve on GLV-1h153, since it appears to be a promising oncolytic agent, based on the data thus far. That’s good news for the San Diego biotech company, Genelux Corporation, who were involved with this oncolytic research. It’s still very early days, but the data looks promising enough to pursue clinical trials in humans further. A phase I trial has recently been completed by the Royal Marsden Cancer Centre in the UK, with preliminary data presented at ASCO earlier this year.