Our Science

Our Science

Platform

platON™ is our proprietary chemistry platform based on a library of decoy oligonucleotides that generate disruptive compounds acting on intracellular DNA-binding targets.

A powerful and versatile platform,  platON™ uses three components, a sequence of double-strand oligonucleotides, a linker, and – when appropriate – a cellular uptake facilitator. Each of these three components is modifiable to generate various compounds expressing different properties and/or activities, with the common feature of targeting tumor DNA repair pathways through a decoy mechanism with an agonist effect.

platON™ has already generated two very innovative molecules: AsiDNA™ and VIO-01

Pipeline

DDR Targeting Molecules

AsiDNA™ is a short double-stranded DNA fragment (oligonucleotide) acting as a decoy and mimicking double-strand breaks in the DNA of the tumor cell. AsiDNA ™ molecules trigger false DNA break signals to activate and attract DNA repair proteins, which prevents their recruitment to the site of actual DNA damage. As a result, damage to tumor cell DNA remains unrepaired. As cancer cells have lost the ability to regulate cell division, they will continue dividing with damaged DNA, ultimately leading to cancer cell death.

Early research indicates that AsiDNATM:

  • Does not cause resistance and reverses resistance to other treatments
  • All targeted therapies are faced with the phenomenon of acquired resistance. AsiDNA™ acts upstream of an essential double-strand break repair pathway, preventing tumor cells from using another protein to resist its action, thereby not causing any resistance.
  • AsiDNA™ has also demonstrated the ability to stop, and even counter resistance to other targeted treatments such as the PARPi, when used in combination.

Becomes more effective the more it is used

  • AsiDNA™ encourages, hyper-activates and diverts a natural biological process essential for tumor cell survival, which it cannot stop and becomes increasingly effective as the cells exhaust the ability to respond to DNA damage.

VIO-01 is the second candidate harnessed from Valerio’s propriety platform of DNA decoy therapeutics and is designed to be a next-generation pan-DDR DNA decoy.

While PARP inhibitors have been a significant advance in cancer treatment, the class still has several limiting factors, particularly the rapid onset of resistance. As a next-generation pan-DDR DNA decoy, VIO-01 is designed to abrogate several DNA repair pathways and trigger a robust immune response by activating the innate immune response through the STING pathway. The STING pathway plays a critical role in detecting DNA abnormalities and activating the immune system to target and destroy cancer cells.

VIO-01 is currently undergoing proof-of-concept IND-enabling preclinical studies, alone and in combination with cancer immunotherapies.

For more information on VIO-01, please see our presentation from the PARP & DDR Inhibitors Summit 2020 and our abstract at the AACR Virtual Meeting 2023.

DecoyTAC Molecules

DecoyTAC – Targeting Oncogenic DNA interacting proteins (such as Transcription Factors)

Mechanism of Action of DecoyTAC

Success

Belinostat is a histone deacetylase inhibitor (HDACi). It has been assessed in several clinical trials as a sole treatment (monotherapy) or in combination with other anti-cancer treatments for hematological cancers and solid tumors. Its anti-cancer activity is associated with the inhibition of cell proliferation, the induction of apoptosis (programmed cell death), the inhibition of angiogenesis and the induction of cellular differentiation.

Beleodaq® is the commercial name of belinostat for injection.

Beleodaq® has been marketed in the United States by Spectrum Pharmaceuticals (SPPI)  since 2014 in the framework of a conditional FDA approval obtained in July 2014.

In March 2019, Acrotech Biopharma LLC, a fully-owned subsidiary of Aurobindo Pharma, acquired from Spectrum Pharmaceuticals (SPPI) the license to belinostat for certain territories, including the United States, Canada, Mexico, and India. In April 2020, Valerio Therapeutics granted Acrotech a royalty-free license to belinostat in all other territories, as well as transfer certain IP and know-how related to belinostat in all its forms. As part of this transaction, Valerio Therapeutics’ licensing agreement with Pint Pharma for South America, as well as the contracts with Clinigen plc and iQone for named patient programs in European countries and related agreements, have also been assigned to Acrotech.

This transaction completed Valerio Therapeutics’ transition to a company solely focused on development activities in the field of DNA damage response in oncology (DDR).

Why target the DNA Damage Response to fight cancer?

The therapeutic approach targeting the DNA Damage Response (or DDR) is a relatively new field in oncology. Its importance has been hailed by the scientific community by the awarding of the 2015 Nobel Prize in Chemistry to three researchers for their studies on DNA repair mechanisms. Professor Tomas Lindahl, a joint recipient of this Nobel Prize, chairs the Valerio Therapeutics Scientific Committee. The inhibition of DNA repair mechanisms in tumor cells is today recognized as one of the most promising ways of treating cancer.

It is based on the fact that cancer cells accumulate DNA breaks, either due to their uncontrolled proliferation, or following treatments such as chemo- or radiotherapy. Not being able to replicate with damaged DNA, their survival is highly dependent on the DNA repair mechanisms, which activate a complex cascade of proteins detecting, signaling, and repairing the breaks. When these mechanisms are impaired, the cancer cells are deprived of the ability to repair their DNA, which leads to their death, when they try to replicate with damaged DNA.

The DNA Damage Response (DDR)

DNA damage response is a sophisticated cascade of cellular events that can be summarized, in a very simplified manner, into three stages:

  • Detection and identification of the damage with “sensor” proteins such as PARP.
  •  Signaling with “transducer” proteins such as DNA-PK, ATR, etc. whose role is essential in coordinating the most appropriate response, repair of the DNA break, or destruction of the cell if the damage is too extensive.
  • Repair with effector proteins such as RAD, POLQ, etc. which will appropriately repair the DNA molecule (resection, replication, insertion, etc.)
Therapeutic Targeting Of The DNA Damage Response (DDR) To Treat Cancer
  • The DNA repair process is a molecular mechanism activated to restore genomic integrity
  • Mutations in genes found in cancer cells can lead to the loss in function of one or more DNA repair pathways, causing cells to become hyper-dependent on the remaining pathways
  • Inhibiting the remaining repair pathways (synthetic lethality) causes further damage to the DNA, turning single-strand breaks into double-strand breaks and triggering cell death
  • There are five PARP inhibitors (base excision repair mechanism) already on the market generating >$3.5B (2022): olaparib (AZ), niraparib (GSK), rucaparib (Clovis Oncology), pamiparib (BeiGene) and talazoparib (Pfizer)
Addressing The Severe Limitations With Current DDR Therapies