Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

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:

  1. imaging potential by using several carrier free radionuclide probes
  2. 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, preliminary data presented at ASCO earlier this year.

  1. Press release – Gruener source ↩
  2. Press release – Haddad source  ↩

5 Responses to “New developments in the biology pancreatic cancer”

  1. biotechbaumer

    Interesting results about EGFR and KRAS in pancreatic cancer! What are your thoughts on the practical issues with development of an anti-EGFR drug to treat earlier stages of the disease? Aren’t drugs normally tested in the late-stage setting and then only if successful, developed for front-line therapy? Even with a strong scientific rationale, it might be difficult to recruit patients and convince doctors to test a drug in in patients that have plenty of other options for therapy. I think this might be an interesting issue going forward as we begin to develop drugs tailored for cancers that are at a particular stage of the tumorigenic process.

    • maverickny

      Yes, the classic R&D development is that drugs are usually tested in metastatic disease and then moved up earlier in the disease if they show good efficacy:side effect profile.  It’s a painstakingly slow way of showing progress!

      Tarceva, an EGFR inhibitor, is already approved for treatment of metastatic pancreatic cancer, so I do think that evidence combined with the new data, suggests that it might be worth testing earlier, especially when you consider it’s an oral therapy and has been shown to be viable as a maintenance therapy, tolerability wise, in EGFR mutated lung cancer.  Certainly, I think a trial would be worthwhile considering.

      We need to think outside the box on clinical trials and start considering logical therapies earlier in the disease, I think.  Look at the I-SPY concept in neoadjuvant breast cancer – some of those therapies were not tested in metastatic disease before the  trial began, although the scientific rationale was certainly there. 

      • biotechbaumer

        I was more interested in the situation where a drug might not show efficacy in advanced cancer but would have an effect in earlier stages of the disease. Perhaps I made a mistake here but I was assuming that similar to lung cancer, KRAS is a negative biomarker for EGFR inhibitor efficacy in pancreatic cancer. The paper quoted here is now showing that inhibiting EGFR would actually have an effect in KRAS mutant pancreatic cancer, but ONLY at earlier stages of the disease.

        It’s an interesting theory to consider that tumors might depend on certain oncogenes only at certain stages of the disease (ie. initiation vs. progression). Down the line, one might think we will stratify patients based on both their genotype and stage of disease, in order to maximize potential drug efficacy.

        • maverickny

          I’m not sure if KRAS is a negative biomarker in pancreatic cancer, will look and see what is in the literature as that is an interesting question… it might be more like colon than lung cancer, where KRAS does matter for EGFR inhibitors such as cetuximab and panitumumab.

          This paper is indeed suggesting that KRAS is involved earlier not later in the disease… it reminds me of VEGF in which the reverse has been shown to be true, ie it appears to matters in metastatic but not adjuvant disease, so your comment that both genotype and stage of disease is very pertinent methinks.

          There was some other research from Vogelstein’s group that showed different pathways or potential targets were involved in carcinogenesis of the tumour they looked at (I forget which one) at different points in the tumour development from benign adenomas through to metastatic tumours – fascinating stuff.  It certainly does speak to the idea that we need to rethink what should be targeted at what point in tumour life cycle more.

        • maverickny

          Looking at Pubmed briefly, there was a recent paper suggesting that KRAS mutations may limit the effectiveness of erlotinib in pancreatic cancer, so that may well explain the marginal benefit of adding it to gemcitabine in treating the advanced disease.  

          See: as an example.

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