ATX-101 is a cell penetrating peptide comprising the APIM motif as well as cell penetration and nuclear localization domains. In preclinical experiments, it was shown that ATX-101 rapidly penetrates cells and targets PCNA/APIM-containing protein complexes1.

By impairing interactions between PCNA with APIM-containing proteins, ATX-101 potentiates the action of several anti-cancer drugs. These include DNA damaging drugs, microtubulin targeting drugs, molecular targeted agents (e.g. p38, MAPK, EGFR inhibitors and others) and g-irradiation (>25 all together). In vivo, ATX-101 has shown proof-of-concept in blood and solid tumor animal models in combination with several clinically relevant drugs. Finally, ATX-101 shows strong anti-cancer action in myeloma patient-derived bone marrow samples ex vivo.

Because PCNA is an important scaffold protein involved in multiple cellular processes, targeting PCNA with ATX-101 (an APIM-peptide) leads to significant changes in gene expression, in the proteome/kinome status and in cellular metabolism. These changes include DNA repair and tolerance mechanisms, DNA damage signaling, MAPK/AKT/ERBB2/EGFR signaling and shifts in the apoptotic response. For example, see the scheme below for actions revealed in bladder cancer cells treated with cisplatin in combination with the APIM-peptide.

pipeline atx101 1

Figure 1. Mode of action for the increased apoptosis seen in bladder cancer cells in vivo (rats) and in vitro treated with APIM-peptide (ATX-101) in combination with cisplatin2. In addition, ATX-101 re-sensitizes cisplatin-resistant bladder cancer cells to treatment2.

In multiple myeloma cells, ATX-101 as a single agent induce apoptosis in the absence of cell division1.

Following successful preclinical development, ATX-101 is currently being tested as a single agent intravenous therapy in a phase I study involving patients with advanced solid tumors. The study aims to analyze the safety (primary endpoint), efficacy and pharmacokinetics (secondary endpoints) of escalating doses of ATX-101 in up to 36 patients. The study is being conducted by APIM’s fully owned Australian subsidiary Therapim Pty Ltd.

ATX-101 lead indications for future clinical testing include multiple myeloma (single agent) and bladder cancer (Gemcitabine/Cisplatin or MVAC combination). However, multiple other development possibilities (e.g. with targeted agents) are also possible owing to the platform development possibilities of this intervention point.

For more information on the mechanism of ATX-101, see Intervention Point or Publications. A 1-page flyer describing the technology is also available here.