Science

Novel first-in-class oncology asset portfolio underpinned by an in-depth understanding of target receptor biology and a rational approach to drug design.

The research programme which underpins Modulus Oncology was recently published here.

Over the last 10 years, a growing body of evidence and scientific literature has been generated to demonstrate the role of both the AM2 receptor and its corresponding ligand, adrenomedullin (AM or ADM), in a wide range of cancers (1-5). Expression levels of adrenomedullin are indicative of a more aggressive cancer sub-type and confer a worse prognosis.  Studies have demonstrated higher adrenomedullin in pancreatic cancer patients compared to controls and it is thought that high serum AM levels in atypical onset diabetes patients can be predictive of pancreatic cancer development (6-8).

Adrenomedullin is a member of the calcitonin peptide family that also includes calcitonin, calcitonin-gene-related peptide (CGRP), and amylin. It is a vasodilator peptide hormone initially isolated from adrenal medulla in 1993 (9). In humans, AM has an important role not only in the maintenance of blood pressure and other key biological functions, but importantly it plays a key role in cancer.

A key research paper on the adrenomedullin receptors and their respective receptor modifying proteins (RAMPs) was published in 1998 (10). The calcitonin-like receptor (CLR) interacts with three different RAMPs. CLR and RAMP1 form the receptor termed the calcitonin gene related peptide (CGRP) receptor, which is involved in the body’s response to pain. This receptor has been successfully targeted with small molecule antagonists approved for the treatment of migraine (11). It is the adrenomedullin receptors (and specifically the AM2R) which form the basis of the research at Modulus Oncology. CLR and RAMP2 form the adrenomedullin 1 receptor (AM1R). This receptor is involved in blood pressure regulation. CLR and RAMP3 form the adrenomedullin 2 receptor (AM2R).  This receptor is involved in cancer development and spread. Both the AM1R and AM2R and their corresponding RAMPs along with other important receptors in this family is shown in figure 1.

Figure 1

The Modulus compounds provide potent selective blocking of the AM2 receptor with little or no effect on the related AM1 receptor.

Both the AM1R and AM2R share a high degree of structural homology but perform very different biological functions. The AM2 receptor is involved both in signalling between tumour cells, and between the tumour and the host (12,13).  Tumour-derived adrenomedullin is associated with up-regulation of the AM2 receptor in host tissues surrounding tumours. This host expression of the receptor is key to tumour development and spread. This has been demonstrated in knock-out models (14,15). In pancreatic tumours adrenomedullin and AM2 expression both increase with tumour severity grade (8). Preclinical studies have shown that reduction in AM2 receptor expression either in tumours or in the host, or modulation of the receptors with peptides or antibodies leads to reduction in cancer cell growth in vitro and in vivo (16-18).

After five years of research and development, the academic team at TUOS have created a potent AM2R antagonist which has excellent selectivity over the AM1R and which has been validated as a development candidate (SHF-1036). This asset will be developed further by Modulus Oncology, which retains the IP for this and other small molecules in the family and benefits from the deep insights of the founding scientific team.

In vitro and in vivo anticancer effects of the Modulus small molecule AM2R antagonists have been demonstrated.  Additional information can be provided on demand.

Reference List

  1. Zudaire, E., Martı́nez, A., & Cuttitta, F. (2003). Adrenomedullin and cancer. Regulatory Peptides, 112(1–3), 175–183. https://doi.org/10.1016/s0167-0115(03)00037-5
  2. Tsuchiya K, et al. Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization. Int J Oncol. 2010; 36(6):1379–86. Epub 2010/04/30. https://pdfs.semanticscholar.org/e72a/b8d7dc35fef49accc253fbdc86cfb3d0f8bb.pdf?_ga=2.245207745.515678814.1599236223-414993857.1599236223
  3. Nouguerede E, et al. Expression of adrenomedullin in human colorectal tumors and its role in cell growth and invasion in vitro and in xenograft growth in vivo. Cancer Med. 2013; 2(2):196–207. Epub 2013/05/02. https://doi.org/10.1002/cam4.51.
  4. Berenguer-Daize C, et al. Adrenomedullin blockade suppresses growth of human hormone-independent prostate tumor xenograft in mice. Clin Cancer Res. 2013; 19(22):6138–50. Epub 2013/10/09. https://doi.org/10.1158/1078-0432.CCR-13-0691.
  5. Greillier L et al Functional Analysis of the Adrenomedullin Pathway in Malignant Pleural Mesothelioma . J Thorac Oncol 2016 Jan;11(1):94-107. doi: 10.1016/j.jtho.2015.09.004. https://www.jto.org/action/showPdf?pii=S1556-0864%2815%2900009-X
  6. D’Angelo, FA, et al. Adrenomedullin in pancreatic carcinoma: a case-control study of 22 patients. Integr Cancer Sci Therap. 2016;3(2):390-392.DOI:10.15761/ICST.1000175. https://www.oatext.com/pdf/ICST-3-175.pdf
  7. Raghuwansh PS et al New insights into pancreatic cancer-induced paraneoplastic diabetes Nature Reviews Gastroenterology & Hepatology 10, pages 423–433 (2013) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932322/
  8. Görgülü K et al. A Star of Connection Between Pancreatic Cancer and Diabetes: Adrenomedullin. Journal of the Pancreas. Sep 2015;16(5):408-412. https://pancreas.imedpub.com/a-star-of-connection-between-pancreatic-cancer-and-diabetesadrenomedullin.pdf
  9. Schubert, M.L. and Chu, S. (2013). Handbook of Biologically Active Peptides (Second Edition). Academic Press. https://doi.org/10.1016/B978-0-12-385095-9.00158-5
  10. McLatchie, L. M., Fraser, N. J., Main, M. J., Wise, A., Brown, J., Thompson, N., Solari, R., Lee, M. G., & Foord, S. M. (1998). RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature, 393(6683), 333–339. https://doi.org/10.1038/30666
  11. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-migraine
  12. Larráyoz, I. M., Martínez-Herrero, S., García-Sanmartín, J., Ochoa-Callejero, L., & Martínez, A. (2014). Adrenomedullin and tumour microenvironment. J Transl Med, 12(1). https://doi.org/10.1186/s12967-014-0339-2
  13. Siclari VA et al Tumor-expressed adrenomedullin accelerates breast cancer bone metastasis . Breast Cancer Research (2014) 16:458 https://breast-cancer-research.biomedcentral.com/track/pdf/10.1186/s13058-014-0458-y
  14. Dackor, R., Fritz-Six, K., Smithies, O., & Caron, K. (2007). Receptor Activity-modifying Proteins 2 and 3 Have Distinct Physiological Functions from Embryogenesis to Old Age. J. Biol. Chem., 282(25), 18094–18099. https://doi.org/10.1074/jbc.m703544200
  15. Dai, K., Tanaka, M., Kamiyoshi, A., Sakurai, T., Ichikawa-Shindo, Y., Kawate, H., Cui, N., Wei, Y., Tanaka, M., & Kakihara, S. (2020a). Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts. Oncogene, 39(9), 1914–1930. https://doi.org/10.1038/s41388-019-1112-z
  16. Kaafarani I et al Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice FASEB J June 22, 2009, doi:10.1096/fj.08-127852. https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.08-127852
  17. Ishikawa T et al Adrenomedullin antagonist suppresses in vivo growth of human pancreatic cancer cells in SCID mice by suppressing angiogenesis Oncogene. 2003 Feb 27;22(8):1238-42. https://www.nature.com/articles/1206207.pdf
  18. Xu M et al Adrenomedullin promotes the growth of pancreatic ductal adenocarcinoma through recruitment of myelomonocytic cells. (2016) Oncotarget, Vol. 7, (34) 55043-55056. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342400/pdf/oncotarget-07-55043.pdf