Pipeline

   Therapeutic Molecular Clusters (TMCs) are created when a single atomic element  forms a stable cluster comprising a defined number of atoms. TMCs are individually unique entities with highly specific physical, chemical and biological properties and represent a totally new therapeutic modality.

TMCs are highly stable in very high temperatures and a broad range of pH . This class of molecule is not metabolized, is eliminated completely and freely diffuses through the body-across the blood brain barrier and into avascular structures. ARJUNA owns patents covering the manufacture and use of multiple TMC molecules. We are actively developing a pipeline of further TMC molecules for cancer and eventually non-cancer indications.

   Cancer cells require large amounts of energy, so remodel the cellular energy apparatus to increase oxidation state leading to generation of toxic by-products such as reactive oxygen species (ROS). This metabolic reprogramming has been implicated in refractory and relapsed disease and shaping of the microenvironment in solid cancers. In general, more aggressive tumours are associated with greater energetic remodeling and more ROS generation. This poses a threat to the integrity of the cancer cell, countered by two redundant antioxidant systems the Glutathione (GSH)- and Thioredoxin (Trx)-dependent pathways. An effective way to treat tumors is to irreversibly block both of them simultaneously. Experimental and therapeutic experience has shown that blocking only one is insufficient because one active system is enough for tumor survival, a reason why inhibitors of these pathways have shown limited success in the clinic. Uniquely, the TMC Ag5 irreversibly blocks both the GSH and Trx-dependent pathways, making it a highly active therapeutic agent. 

   Because TMC-Ag5 only acts to catalyse ROS generated by the cancer cell, its action against the antioxidant pathways only occurs in cancer cells with the highest ROS levels, in a process that we call metabolic synthetic lethality. As a consequence, Ag5 will preferentially kill cancer cells, but will spare normal cells due to their REDOX homeostasis, leading to efficacy in the most difficult to treat cancers along with minimal off-target effects.

   We are investigating biomarkers that allow us to identify cancers with the highest levels of ROS, and therefore the most sensitivity to Ag5. Preclinical testing of Ag5 shows significant tumor killing efficacy in KRAS mutant cancers. In fact, KRAS expression sensitizes cells to Ag5 through increased ROS levels and Ag5 increases sotorasib activity in G12C mutant cells. We have compelling evidence that oncogenic drivers and other biomarkers will allow us to identify cancers for treatment with Ag5 beyond those with mutant KRAS. We therefore believe that eventually, the patient population that is addressable by Ag5 treatment will not only include, but will go beyond KRAS mutant cancers. Ag5 is currently in preclinical testing.

•  Indication: Overcoming solid tumour cisplatin resistance

•  MoA: DNA intercalator producing disruption of topoisomerase-DNA complex formation    

We have shown that clusters of three atoms such as Ag3 can augment

chromatin accessibility. This effect only occurs during DNA replication.

Administration of both Ag3 with Cisplatin increases the cytotoxic effect of

DNA-acting drugs on human lung carcinoma cells. In mice with orthotopic

lung tumors, the co-administration of Ag3 increases the amount of Cisplatin

(CDDP) bound to the tumor DNA by fivefold without modifying CDDP levels

in normal tissues. As a result, CDDP co-administered with Ag3 more

strongly reduces the tumor burden. This effect has also been shown for

other chemotherapies. Evidence of the significance of targeting chromatin

compaction to increase the therapeutic index of chemotherapy is one of the

future applications we are going to explore further in the new field of

Therapeutic Molecular Clusters. Ag3 is currently in preclinical testing.

   10.5 Million patients a year are given radiotherapy worldwide. Efficacy is

limited by resistance of cancer cells to the radiation dose that is necessarily

limited to prevent damage to surrounding tissue. The effects of this damage

are huge-particularly where radiotherapy is administered to pediatric

patients who then go on to develop radiation-induced cancers many years

later. Radioligand drugs are an alternative way to target the cytotoxic

effects of radiation to cancer cells, but this approach in the past has been

limited by poor efficacy.

   Ag3 and Ag5 each act to make cancers more sensitive to radiation by

separate, complementary mechanisms as well as protecting non-cancer

cells by inducing expression of anti-ROS genes. This could allow more

cells to be killed, or to allow less radiation to be given, reducing off-target

effects. Of particular relevance is the fact that TMCs freely cross the blood

brain barrier, making them ideal for augmenting cranial radiotherapy.

TMCs both sensitize tumors to radiotherapy up to 5x with our in vitro

studies and protect non-dividing cells from harm from radiation.