The Ralph Bates Pancreatic Cancer Research Fund

About the Fund

The Ralph Bates Pancreatic Cancer Research Fund is a registered charity, number 1007819.  The trustees are Virginia Bates, Dr John Glees MD FRCR, Michael Bridge FCA, Sharon Sullivan, Les Biggs ACIS (Secretary) and Sir Peter Blake CBE,RDI,RA. 

The main objective of our Charity is to provide funds for research into causes and cures for pancreatic cancer. Below is a summary of some of the reserach work we have funded at St George’s University of London in Tooting, South West London.

Our research.

The Fund has supported research at St George’s University of London in Tooting, South London for many years into the effect on pancreatic cancer cells of various combinations of drugs.  Prof. Gus Dalgleish, one of the UK’s foremost cancer specialists has driven and directed this research.  Below is a summary of his teams’ achievements over the last five years.

Over the last five years we have continued to pursue new and complimentary approaches to improve the lot and quality of life of pancreatic cancer patients.  This has included screening agents which may have at least an additive effect with Gemcitabine (a current gold standard treatment for pancreatic cancer, which is far from ideal). 

One of these approaches led to a clinical study following pre-clinical data indicating that a non-specific vaccine, Mycobacterium vaccine, could enhance Gemcitabine and anecdotal observations of marked improvement in patients who are on this combination.  A company called Immodulon has resurrected a Mycobacterium vaccine and it is now in a randomised phase II study with Gemcitabine in patients with advanced pancreatic cancer.

The second major discovery was to show that Lenalidomide, aThalidomide derived drug now approved for the treatment of myeloma, could reverse the inevitable resistance of cell lines when exposed to Gemcitabine.  Again, clinical anecdotes suggest that this combination is very effective and very well tolerated.  Lenalidomide has been recommended as a second line trials candidate for use in pancreatic cancer patients by a pancreatic expert U.K. board.  Independently Lenalidomide has also been shown to enhance responses to vaccines, so combining it with Gemzar and the vaccine is a logical next step.

We have also shown that some very simple cheap and non-toxic agents have surprising activity against pancreatic cell lines.  We published that Doxycycline is able to induce cell death in pancreatic cells, which is very unexpected.1 Doxycycline is a broad spectrum antibiotic with marked anti-inflammatory activity which also inhibits enzymes expressed by tumour cells.  We also screened a large number of Thalidomide analogues and found that two of these were very effective in pancreatic cancer cells.  This was published in Pancreas and the lead author was, again, Mouratidis.2 

It is now becoming widely accepted that a major problem with cancer and particularly pancreatic cancer, is the ability to block anti-tumour immune responses.  A bi-product of looking at the effects of the Thalidomide analogues with Gemcitabine was the realisation that they may inhibit the function of these cells and have essentially two anti-pancreatic cancer effects.  This we were able to show and this was published by Galustian et al in the Cancer Immunology Immunotherapy journal in 2009.3 

Following the successful completion of his PhD by Petros Mouratidis, Rosemary Fryer was appointed to the Ralph Bates Pancreatic Cancer Research Fund studentship.  Her focus was on Gemcitabine and trying to overcome resistance.  This involved a full review of current treatment on pancreatic cancer, which we eventually published.4  In 2010 we wrote up a case report whereby a colleague with metastatic pancreatic cancer had become resistant to Gemcitabine.  Because of our laboratory experiments she was given Lenalidomide as well as the Gemcitabine.  Within two years, not only was this cancer under control but the patient continued to lead a normal working life.5 This patient also had the Mycobacterium vaccine on a compassionate basis and she continued to receive all three agents, with the Gemcitabine being given in much reduced doses and much less frequently than standard protocols.  After four years of treatment she died of a non-related condition and at autopsy there was no evidence of her metastatic pancreatic cancer.  The most remarkable thing about this was the fact that the process was so slow, with only a 25% reduction in her tumour on the CT scan after two years.  An important lesson is that this combination of very low toxicity agents was able to eliminate pancreatic cancer.  This led to a very detailed study looking at the molecular mechanisms that might be underlying this and this became the focus of Rosemary Fryer’s successful PhD, which was published in Anti-Cancer Research in 20116, showing how Gemcitabine and Lenalidomide acted synergistically, with the latter reversing Gemcitabine resistance. 

We have continued to look at the mechanisms of how drugs may be able to control cancer without necessarily utilising classical cytotoxic pathways.  This has resulted in microarray studies of gene expression after treatment with different drugs7, as well as in preclinical models, showing the ability to inhibit metastatic spread through independent mechanisms.8  This has led to a focus of how immunotherapy could enhance the response to other modalities and, in particular, improve outcome and quality of life.9 We have also continued to look for other agents with anti-cancer activity which are non-toxic and in most cases are not being commercially developed.  One of these focussed on the anti-malarial agent, Artusenate, which is widely used for malaria treatment in severe cases.  We were able to show significant anti-cancer activity.10, 11.  Also cannabis derived substances, which are being developed for use in multiple sclerosis, have been shown to have an anti-cancer component.12 

We have continued to look at the way that the immune system can be used to enhance anti-cancer activities and have looked at several different technologies and experiments.13,14,15,16  Work on the Mycobacterium vaccine has shown that it stimulates an innate primitive T-cell response with marked anti-tumour activity, which maybe the main mechanism of action of the vaccine.17

Because of our expertise in cell and pre-clinical models and translation to the clinic, we were delighted to be asked to collaborate with Helmout Modjtahedi, Professor of Cancer Biology at the University of Kingston, who is an expert on cancer signalling pathways.  I became a co-supervisor of his student who has been exploring the effects of a number of different factors in human pancreatic tumour cells.  One new agent was a particular effector of this19 and this has been followed up by a complete review of expression pattern and targeting of HER family members and the IGF-1 receptor in pancreatic cancer.20

With Rosemary Fryer’s successful completion of her PhD, we appointed Alan Levett from a very competitive field to continue the mechanisms of resistance and escape from Gemcitabine by pancreatic cell lines.  He has now established a resistant cell line in order to dissect out the vulnerable pathways, optimising pathways with other agents.  We are also pursuing other leads, such as the susceptibility of this cell lines to Curcumen, which has previously been reported as having activity in colorectal cancer cells.  It would also appear to be pertinent with regards pancreatic cancer. 

We are also investigating the fact that there are several anecdotal reports on patients with pancreatic cancer responding to low dose Naltrexone.  We have found a new mechanism for Naltrexone which may be very pertinent.  Unlike some drugs that have been shown to be synergistic with Gemcitabine, which are currently available but unfortunately very expensive, Curcumin and Naltrexone are available, non-toxic and cheap.

In conclusion, the work of the Ralph Bates Pancreatic Cancer Research Fund to date has led to a number of relatively non-toxic additions to standard treatment, which have made dramatic differences in anecdotal cases.  One of these has been taken up and funded by the company Immodulon with the vaccine drug combination already in a multi-centre randomised study.  Our on-going work has already identified a number of other non-toxic, cheap and widely available agents which many patients are benefitting from and which will hopefully be incorporated into trials in the future

This research is on-going.

References

  1. 1.      Mouratidis PX, Colston KW, Dalgleish AG.  Doxycycline induces caspase-dependent apoptosis in human pancreatic cancer cells.  Int J Cancer. 2007 Feb 15;120(4):743-52.
  2. 2.     Mouratidis PX, Dalgleish AG, Colston KW. Investigation of the mechanisms by which EB1089 abrogates apoptosis induced by 9-cis retinoic acid in pancreatic cancer cells.  Pancreas. 2006 Jan;32(1):93-100.
  3. 3.     Galustian C, Meyer B, Labarthe MC, Dredge K, Klaschka D, Henry J, Todryk S, Chen R, Muller G, Stirling D, Schafer P, Bartlett JB, Dalgleish AG. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells..  Cancer Immunol Immunother. 2009 Jul;58(7):1033-45
  4. 4.     Fryer, A, Galustian C and Dalgleish, A.  Recent advances and developments in treatment strategies against pancreatic cancer.  Curr Clin Pharmacol. 2009 May;4(2):102-12.
  5. 5.     Liu WM, Nizar S, Dalgleish AG.  Gemcitabine and lenalidomide combination in a patient with metastatic pancreatic cancer: a case study.  Med Oncol. 2010 Jun;27(2):430-3.
  6. 6.     Fryer RA, Barlett B, Galustian C, Dalgleish AGMechanisms underlying gemcitabine resistance in pancreatic cancer and sensitisation by the iMiD™ lenalidomide.  Anticancer Research. 2011, 31(11):3747-56]
  7. 7.     Liu WM, Lauz H, Henry J, Dalgleish AG, Galustian C. A microarray study of altered gene expression in colorectal cancer cells after treatment with immunomodulatroy drugs: differences in action in vivo and in vitro.  Mol Biol Rep. 2010 Apr;37(4):1801-14.
  8. 8.     Liu WM, Fowler DW, Smith P, Dalgleish AG.  Pre-treatment with chemotherapy can enhance the antigenicity & immunogenicity of tumours by promoting adaptive immune responses.Br J Cancer. 2010 Jan 5;102(1):115-23.
  9. 9.     Liu WM, Meyer B, Dalgleish AG.  How immunotherapy can enhance the response to other modalities and improve outcome and quality of life.  J BUON. 2009 Sep;14 Suppl 1:S103-9
  10. 10.   Liu WM, Gravett AM, Dalgleish AGThe anti-malarial agent artesunate possesses anti-cancer properties that can be enhanced by combination strategies. Find all citations by this author (default).International Journal of Cancer. 2011, 128(6):1471-80]
  11. 11.    Gravett AM, Liu WM, Krishna S, Chan WC, Haynes RK, Wilson NL, Dalgleish AGIn vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents.  Cancer Chemotherapy and Pharmacology 2011, 67(3):569-77Find all citations by this author (default).Or filter your current search Find all citations by this author (default).
  12. 12.   Liu WM, Fowler DW, Dalgleish AG.   Cannabis-derived substances in cancer therapy–an emerging anti-inflammatory role for the cannabinoids.  Current Clinical Pharmacology 2010, 5(4):281-7
  13. 13.   Liu WM, Dennis JL, Fowler DW, Dalgleish AGThe gene expression profile of unstimulated dendritic cells can be used as a predictor of function.  International Journal of Cancer. Journal International du Cancer 2012, 130(4):979-90
  14. 14.   Kovalcsik E, Lowe K, Fischer MDalgleish A, Bodman-Smith MDPoly(I:C)-induced tumour cell death leads to DC maturation and Th1 activation.  Cancer Immunology, Immunotherapy : CII 60(11):1609-1624 Nov 2011
  15. 15.   Liu WM, Fowler DW, Gravett AM, Smith P, Dalgleish AG. Supernatants from lymphocytes stimulated with Bacillus Calmette-Guerin can modify the antigenicity of tumours and stimulate allogeneic T-cell responses.  British Journal of Cancer. 2011, 105(5):687-93
  16. 16.   Liu WM, Dennis JL, Gravett AM, Chanthirakumar C, Kaminska E, Coulton G, Fowler DW, Bodman-Smith M, Dalgleish AG.   Supernatants derived from chemotherapy-treated cancer cell lines can modify angiogenesis.  British Journal of Cancer 2012, 106(5):896-903
  17. 17.   Fowler DW, Copier J, Wilson N, Dalgleish AG, Bodman-Smith MD  Mycobacteria activate γδ T-cell anti-tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy. CII 2012, 61(4):535-47
  18. 18.   Stebbing J, Dalgleish A, Gifford-Moore A, Martin A, Gleeson C, Wilson G, Brunet LR, Grange J, Mudan SAn intra-patient placebo-controlled phase I trial to evaluate the safety and tolerability of intradermal IMM-101 in melanoma.  Annals of Oncology : Official Journal of the European Society for Medical Oncology / ESMO [2012, 23(5):1314-9]
  19. 19.   Ioannou N, Dalgleish AG, Seddon AM, Mackintosh D, Guertler U, Solca F, Modjtahedi H. Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells.  British Journal of Cancer (2011)105, 1554-1562.
  20. 20.   Expression pattern and targeting of HER family members and IGF-IR in pancreatic cancer. Ioannou N, Seddon AM, Dalgleish A, Mackintosh D, Modjtahedi H.  Front Biosci. 2012 Jun 1;17:2698-724

Prof Gus Dalgleish.

26th November 2012         Find all citations by this author (default).

 

 

And more research at St George’s;

In April 2009, we started additional research at St George’s focusing on the effect of protein control on cancer cells.   Dr Androulla Elia a senior research Fellow who is leading this team (which includes Reka Chakravarthy, Judith Cartwright and Satvinder Mudan), has prepared the following article to explain the research. It’s a bit technical but very readable!

Over the past year we have been using different combinations of treatments to induce pancreatic cancer cells in tissue culture to undergo a process that is known as apoptosis, a form of “programmed” cell death.  We have recently had some very promising results when we treat resistant cancer cells with a combination of two reagents (a substance used to detect the presence of another) called TRAIL and Celastrol. 

TRAIL is known as a cytokine, a hormone-like chemical that the human body can normally produce to regulate the immune system.  It has tremendous potential for use in chemotherapy as it is able to target and kill cancer cells specifically, without doing damage to normal tissues. This is because TRAIL uses a molecule on the cell surface known as a receptor, which allows signals into the cell to switch on apoptosis. TRAIL receptors are commonly found on most tumour cells including pancreatic cancer cells. Unfortunately tumour cells can make receptors that still bind TRAIL but are unable to pass the signal on (these are known as decoy receptors). Some cancer cells have lots of these decoy receptors. In addition, many tumours activate processes that protect the cells from dying even when there are signals from active TRAIL receptors. Thus, when we initially treated some of our pancreatic cancer cells with TRAIL on its own we saw very little effect. 

Celastrol is an ingredient of herbal medicine that is extracted from the plant Tripterygium wifordii – more dramatically known as the Chinese God of Thunder Vine. It was recently reported to be able to inhibit a molecule known as TAK-1 that is involved in activating survival pathways in tumour cells. However when we treated pancreatic cancer cells with Celastrol alone, again we did not observe any apoptosis. 

The exciting breakthrough came when we used both TRAIL and Celastrol together. Then we saw the cells die very quickly! What we believe is happening is that Celastrol removes a block to the actions of TRAIL, making the cell death signal stronger than with TRAIL alone. In other words Celastrol makes TRAIL more effective and so the cells undergo apoptosis.  We would now like to establish the precise mechanism behind how these two reagents are working together, and then go on to use TRAIL and Celastrol on even more resistant pancreatic cancer cells. Of course the ultimate aim is to transfer our findings to the clinic, for the ultimate benefit of future pancreatic cancer patients

Dr Androulla Elia.             

August 2010.

 

 

 

This research is also on-going.