Science

Developing next generation cancer therapies: Targeting a novel immune checkpoint while preventing collateral damage to normal tissues.

Paradigm Shift Therapeutics (PSTx) is developing small molecule drugs that target CD47:

Award winning work in the Roberts Lab at the National Cancer Institute (NCI) showed that blocking CD47 selectively protects normal tissue from radiation or chemotherapy damage while enhancing the effect of the therapy on the tumor. Our work is based on the discoveries of co-founder Dr. Thomas Miller while he was an NCI research fellow in the lab of PSTx collaborator Dr. David Roberts.  In addition to focusing on cancer treatments, PSTx is also pursuing CD47 modulators for the treatment of accidental medical and occupational radiation exposure (e.g. the Fukushima Daichi disaster).

Developing multiple classes of molecules targeting CD47 

CD47 is a multi-functional and widely expressed cell-surface molecule:

  1. CD47 acts as a receptor for its matricellular ligand thrombospondin-1 (TSP1) to regulate cell survival/death signaling pathways in a wide range of normal tissues notably in T cells [Isenberg 2008, Li 2001/2002, Miller, 2013].

  2. CD47 is a marker of ‘self’—the so called “don’t eat me” signal, which acts through the inhibitory phagocyte receptor, SIRPα [Brooke 2004, Chao 2012].

 

PSTx is developing multiple classes of CD47 inhibitors that significantly impact tumor survival through activation of antitumor immunity, enhancement of direct tumor cell killing, and normal tissue protection in the context of chemo/radiation therapy [Maxhimer et al. 2009; Soto-Pantoja et al. 2013 & 2014; Liu et al. 2015; Vonderheide 2015].

  1. Brooke G1, Holbrook JD, Brown MH, Barclay AN. Human lymphocytes interact directly with CD47 through a novel member of the signal regulatory protein (SIRP) family. J Immunol. 2004 Aug 15;173(4):2562-70.

  2. Chao, MP; Weissman, IL; Majeti, R. The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Current Opinions in Immunology 2012, 24:225-232. 

  3. Isenberg, J. S.; Maxhimer, J. B.; Hyodo, F.; Pendrak, M. L.; Ridnour, L. A.; DeGraff, W. G.; Tsokos, M.; Wink, D. A.; D., R. D., Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury. Am. J. Pathol. 2008, 173, 1100-1112. PMID: 18787106. 

  4. Li Z, He L, Wilson K, Roberts D. Thrombospondin-1 inhibits TCR-mediated T lymphocyte early activation. J Immunol. 2001 Feb 15;166(4):2427-36.

  5. Li Z, Calzada MJ, Sipes JM, Cashel JA, Krutzsch HC, Annis DS, Mosher DF, Roberts DD. Interactions of thrombospondins with alpha4beta1 integrin and CD47 differentially modulate T cell behavior. J Cell Biol. 2002 Apr 29;157(3):509-19. 

  6. Maxhimer, J. B.; Soto-Pantoja, D. R.; Ridnour, L. A.; Shih, H. B.; DeGraff, W. G.; Tsokos, M.; Wink, D. A.; Isenberg, J. S.; D., R. D., Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling. Sci. Transl. Med. 2009, 1, 3ra7. PMID: 20161613

  7. Miller TW, Kaur S, Ivins-O'Keefe K, Roberts DD. Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation. Matrix Biol. 2013 Aug 8;32(6):316-24.

  8. Soto-Pantoja, D. R.; Stein, E. V.; Rogers, N. M.; Sharifi-Sanjani, M.; Isenberg, J. S.; Roberts, D. D., Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47. Expert opinion on therapeutic targets 2013, 17 (1), 89-103. PMID: 23101472. 

  9. Soto-Pantoja DR, Terabe M, Ghosh A, Ridnour LA, DeGraff WG, Wink DA, Berzofsky JA, RobertsDD. CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Res. 2014 Dec 1;74(23):6771-83.

  10. X. Liu, Y. Pu, K. Cron, Li. Deng, J. Kline, WA. Frazier, H. Xu, H. Peng, Y-X Fu & MM. Xu CD47 blockade triggers T cell–mediated destruction of immunogenic tumors. 2015. Nat. Med. 21 (10) 1209-5. PMID: 26390038.

  11. RH. Vonderheide.  CD47 Blockade as another immune checkpoint therapy for Cancer.  2015.  Nat. Med. 21 (10) 1122-23. PMID: 26444633.