Mutant RAS targetable after all

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There has been much pessimism about the possibility of targeting RAS following the apparent failure of farnesyl transferase inhibitors in clinical trials [1]. However given that KRAS is mutated up to 90% in some cancers such as pancreatic ductal adenocarcinoma (PDAC), abandoning the idea of targeting RAS is premature. Recently two different targets which nullify mutated RAS have been validated.

 

Researchers at the Max Planck Institute of Molecular Physiology, Dortmund, Germany have developed small molecule competitive binders of the prenyl-binding protein PDEδ. RAS proteins are farnesylated and this controls their localisation to the plasma membrane which is essential for RAS signalling such that is constitutively activated in cancer. PDEδ binds the farnesyl tail of RAS and facilitates its transport to the plasma membrane. The Max Planck research group have developed a series of compounds with ever greater affinity for the PDEδ pocket that binds RAS. They have shown in pancreatic cancer cell lines with mutated KRAS that these compounds reduce cell proliferation (Figure 1). Deltazinone was their first generation compound and Deltarasin their second generation compound [2, 3].

 

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Figure 1: Proliferation of KRAS mutant cell lines is reduced by PDEδ inhibition. Taken from top two panels of Figure 3 abc of Ref [3]. No changes were made. Creative Commons Attribution 4.0 International (CC BY 4.0).

 

The laboratory of E. Premkumar Reddy (New York) and collaborators have developed a new small molecule called Rigosertib which binds to the RAS-binding domain (RBD) present in proteins that interact with RAS and thus block this interaction, nullifying activated RAS [4]. Rigosertib dramatically reduced the growth of human HCT116 colon cancer cell line implanted as a mouse xenograft. It also reduced the number of Pancreatic Intraepithelial Neoplasia (PanIN) lesions, precursors of PDAC, present in KRAS mutant mice.

 

It will be important to further refine these compounds into leads for preclinical development through to investigational new drug (IND) submission as they are very promising developments for RAS active tumours such as PDAC.

 

Refs

 

  1. Orchard­-Webb D. 2015. Future Directions in Pancreatic Cancer Therapy. JOP. Journal of the Pancreas 16:249­-255.
  2. Zimmermann, Gunther, Björn Papke, Shehab Ismail, Nachiket Vartak, Anchal Chandra, Maike Hoffmann, Stephan A. Hahn, et al. ‘Small Molecule Inhibition of the KRAS-PDEδ Interaction Impairs Oncogenic KRAS Signalling’. Nature 497, no. 7451 (30 May 2013): 638–42. doi:10.1038/nature12205.
  3. Papke, Björn, Sandip Murarka, Holger A Vogel, Pablo Martín-Gago, Marija Kovacevic, Dina C Truxius, Eyad K Fansa, et al. ‘Identification of Pyrazolopyridazinones as PDEδ Inhibitors’. Nature Communications 7 (20 April 2016): 11360. doi:10.1038/ncomms11360.
  4. Athuluri-Divakar, Sai Krishna, Rodrigo Vasquez-Del Carpio, Kaushik Dutta, Stacey J. Baker, Stephen C. Cosenza, Indranil Basu, Yogesh K. Gupta, et al. ‘A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling’. Cell 165, no. 3 (21 April 2016): 643–55. doi:10.1016/j.cell.2016.03.045.
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Latest clinical trials of reovirus in pancreatic cancer patients

Version française

REOLYSIN® is a formulation of human reovirus type 3 Dearing (T3D) which is being developed by Oncolytics Biotech Inc. for a number of cancer indications including pancreatic ductal adenocarcinoma (PDAC) (see here). It has entered clinical trials for pancreatic cancer in combination with a number of drugs including standard chemotherapeutics and newer immune checkpoint targeting antibodies (Pembrolizumab: trade name KEYTRUDA®) (See table 1).

 

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ClinicalTrials.gov links

NCT02620423, NCT01280058, NCT00998322

 

Update of NCT01280058 (NCI-8601) trial based on data collected up to January 19, 2016 from the NCI

http://www.oncolyticsbiotech.com/news/oncolytics-biotech-inc-reports-updated-data-from-randomized-phase-2-study-of-reolysin-in-pancreatic-cancer/?elqTrackId=f8f1f697d24a4f1b8a0b57d84b98e11a&elq=2fe69a4b469249f18ccf3b23e1db27fe&elqaid=15230&elqat=1&elqCampaignId=9

The overall survival rate was increased. A proportion of patients receiving REOLYSIN® were alive beyond three years, whereas no patients in the control group survived beyond one year.

 

Final results from Oncolytics Biotech Inc.’s NCT00998322 (REO 017) Phase II study

http://www.oncolyticsbiotech.com/news/oncolytics-biotech-inc-collaborators-present-final-data-from-reo-017-clinical-study-in-pancreatic-cancer/

http://www.oncolyticsbiotech.com/wp-content/uploads/2015/07/panc-poster-June22-2015.pdf

Overall survival rates were increased and the immune checkpoint protein PD-L1 was demonstrated to be increased in post-treatment tumours. This formed a rationale for the use of Pembrolizumab (KEYTRUDA®) in the new NCT02620423 (REO 024) trial.