Cancer Therapies — Have we been looking the wrong way?
This question was one of the conclusion drawn in article published by Ann Lin et al published in Journal Science Translational Medicine Not Only did the research highlight the importance of Off Target effects of cancer drugs, but it accidentally discovered a new pathway and first ever inhibitor of that pathway.
Cancer treatment has significantly evolved in the last couple of decades from “Kill –all” chemotherapy to targeted drugs to biomarker based therapies to Immuno-Oncology . Despite these advances, a study on probability of success of clinical trials showed oncology had a success rate of 3.4%. With cancer being the leading cause of death of millions around the world, a 3.4% success rate is quite dismal. This leads us to some fundamental questions
Why can’t we reproduce promising preclinical success by the time the drug is set to hit the market?
Have we looked at the problem in a wrong way?
The researchers Ann Lin et al, helped answer these questions in their paper by making 3 very important points:
True Mechanism of Action: The so called targeted therapies were killing the cancer cells but just not in the way they were earlier known to — resulting in off –Target effects. It is possible some of the drugs may have targeted superfluous proteins limiting their efficacy
CRISPR-Cas 9 Mutagenesis has enabled the scientists to eliminate some of the presumed targets like MELK, despite that the drug ( MELK inhibitor ) seems to work on the cancer cells — indicating that MOA of the drug may not be MELK inhibition. The researchers looked at 10 such drugs in preclinical settings aimed at six protein with about 30 trials ongoing
However, to me the most important point the article elucidates is that older methodologies ( eg : RNA interference) of identifying the druggable targets and cancer dependencies have their limitations
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is the foundation of genome editing technology CRISPR-Cas9, wherein researchers can target specific parts and edit DNA precisely and is easier compared to the other technologies available. There are about 25 CRISPR based therapies in early stage trials
With IQVIA 2018 estimating the Global Oncology Spends reaching 200 billion in the next 5 years, the above research gives significant insights on preclinical research in oncology , to not only identify candidates for phase II- III but also the patients who will benefit from them the most.
Given the promising results of CRISPR in the above paper, there are many points that need deeper understanding :
-With the rapid development of CRISPR tech, does it mean the era of older methodologies is over, for now seems to be pointing in that direction, however, CRISPR comes with it’s own set of challenges
-With Big Pharma acquiring companies, investing in CRISPR technology, it may likely help them spend their research dollars more efficiently. Today Pharma in Oncology follows the typical playbook of bringing similar drugs within a pathway — VEGF inhibitors (Sunitinib, Pazopanib, Axitinib) or CDK4 inhibitors or the I/O pathway. CRISPR –CaS9 analysis can also aid in discovering newer pathways adding to their portfolio’s life cycle management
Lastly who will pay for CRISPR based therapies — with exorbitant prices of gene based therapies coming under scrutiny, I would presume the CRISPR based therapies will cost even higher and leading to enormous pressure on healthcare budgets
While we celebrate the wins of this technology, anyone following Oncology will know, the entire dialogue has now shifted to value and affordability and these technologies will fast need to demonstrate that — as the payers and regulators come knocking!
