By Deborah Borfitz 

April 11, 2023 | A small company based in Norway is taking on the global-sized challenge of cancer treatment, notably including solid tumors and hematological malignancies. The means is a promising, highly specific drug, known as ATX-101, whose molecular target orchestrates many different processes in the cells, according to Jens-Peter Marschner, M.D., chief medical officer of APIM Therapeutics, a spinoff from the Norwegian University of Science and Technology (NTNU) where basic research was done. 

The target of ATX-101 is proliferating cell nuclear antigen (PCNA)—a universal regulator of metabolism as well as an essential protein for DNA replication and repair—but the compound acts only on cancer cells while leaving healthy cells undamaged, says inventor Marit Otterlei, professor of molecular medicine at NTNU and founder of APIM Therapeutics. The phase 1 study, published late last year in Oncogene (DOI: 10.1038/s41388-022-02582-6), found that ATX-101 stopped tumors from growing in the majority of 25 terminally ill cancer patients. 

The intent, as with all phase 1 studies, was to assess the safety profile of the novel drug, says Marschner, which was good. The only issue encountered was a mild-to-moderate allergic reaction to infusion of the drug, which self-resolved with or without symptomatic treatment and ATX-101 treatment then resumed. There were no off-target effects, such as the hair loss that is typical with chemotherapy. 

All 25 study participants had solid tumors, most frequently colorectal and non-small cell lung cancer, and were in end-of-life care, he points out. They had an average of four prior systemic treatments and 80% of patients were refractory to the last attempted therapeutics. Disease nonetheless stabilized in 14 of 20 patients (efficacy population with at least one tumor measurement after treatment start) when they were on ATX-101 and disease stabilization persisted over a median period of at least four months.  

ATX-101 is a peptide that contains the APIM binding sequence commonly found in proteins that fixes to PCNA when cells encounter stress, Marschner explains. It impairs signaling pathways from being activated in cells—at least in cancer cells experiencing the stress of a counterattack by the body’s immune system on top of whatever anti-cancer treatment patients may be administered. 

Cancer cells often have DNA damage caused by replication stress, which drives tumor development as some of the mechanisms controlling DNA copy speed are impaired, adds Otterlei. They also handle metabolism differently than normal cells, increasing the rate of glucose consumption and preferentially producing lactate even in the presence of oxygen (so-called “Warburg effect”), and lose apoptotic control so they can survive longer. All these stresses are impaired by ATX-101. 

Discovery of the new binding motif that can block PCNA from binding to proteins responsible for repair of DNA damage and increase cellular metabolism, and thus impede essential stress responses in cancer cells, was done by Otterlei’s research group at NTNU. To usher ATX-101 through the clinical and regulatory stages of development required formation of APIM Therapeutics in 2010. 

Phase 1b/2a studies of the drug are now underway in ovarian cancer patients in Australia and the sarcoma patients in the United States, Marschner reports. Australia has proven to be a quick and economic place to conduct trials relative to Europe and the U.S. and enjoys a strong reputation for the quality of its scientific and medical research.  

Ongoing Trials 

Although the efficacy of ATX-101 proved rather striking in the phase 1 trial, moving forward it will most likely be used as part of combination therapies to better outsmart cancer alongside chemotherapy, radiotherapy, targeted therapies, and possibly immune therapies, says Otterlei. This is now the cornerstone of cancer therapy because it invariably improves patient outcomes. 

The ovarian cancer trial is a proof-of-concept study sponsored by APIM Therapeutics that is enrolling about 80 patients who have failed prior therapies and have tumors sensitive to platinum-based chemotherapies, notes Marschner. It is backed by strong in vivo and in vitro clinical data demonstrating the benefit of the combination of ATX-101 with carboplatin/pegylated liposomal doxorubicin. The study has been discussed with the U.S Food and Drug Administration and is registered on ClinicalTrials.gov.   

The sarcoma study is an investigator-initiated trial being conducted by researchers at Columbia University in New York who were intrigued to learn from the phase 1 study that two patients with sarcoma had “quite long progression-free survival,” he says. One of these was a patient with uterine leiomyosarcoma who was treated for over 17 months and remained stable after 29 months when she was lost to follow-up. 

Although initially intended to be a monotherapy trial of ATX-101, it will probably be modified to be used in combination with chemotherapy, says Marschner. Preclinical data on the efficacy of the combo, generated by Columbia University, will be presented at the American Association for Cancer Research annual meeting in mid-April. 

Being a small company, APIM Therapeutics is selective about the clinical studies it initiates, says Otterlei. Studies for several more clinical indications are under consideration.   

PCNA is relevant in all tumors, Marschner says, so funding is the only real limitation. Based on preclinical and clinical work to date, the company is “very optimistic” that its first-in-class drug could bring benefit to patients with glioblastoma as part of a therapeutic regimen. One of the bigger hurdles has been communicating the role of PCNA among investors who are accustomed to backing less versatile, single-target agents.