NEW YORK – After four years of preclinical research establishing PRDM as a druggable target in cancer, California-based biotech Ariz Precision Medicine is advancing a therapeutic program focusing on lung cancers with altered PRDM genes.
The company emerged from stealth mode in November with $2.5 million in seed funding and is setting its sights on developing PRDM-targeted therapies for lung, ovarian, breast, and gastric cancers, and multiple myeloma. Following on its earlier preclinical research, the company is moving into animal models this year and expects human studies to start in lung cancer this year or early 2022.
The company is part of the University of California, Davis's Venture Catalyst DRIVE Program, which gave the nascent biotech access to the university's labs and other support to research the role of PRDMs in cancer cells. The company is investigating several different cancer types "both solid tumor and hematological, so that we can really identify where PRDMs best fit and present an opportunity," said Ariz CEO Brad Niles.
PRDMs are a family of histone methyltransferases. Although PRDMs are well-studied in academia, Niles said, there aren't any commercialized drugs that target these genes. What Ariz has developed so far is a platform for understanding the mechanism of agents targeting these genes. In their preclinical research, Ariz has found that drugs targeting PRDMs can modulate gene methylation or silencing events that allow cancer to grow.
The platform uses siRNA (small interfering ribonucleic acids) technology to deliver the treatment to cancer cells. Researchers affiliated with Ariz published a study in Nanomedicine in 2011 demonstrating the efficacy of using siRNA to target PRDM14 in breast cancer cells.
That study, done in collaboration with researchers at Auburn University, found that the PRDM14 targeted therapy plus doxorubicin chemotherapy killed 60 percent of breast cancer cells after one dose, whereas chemo alone killed 20 percent of cells.
"The mission has been to prove, first to ourselves and then to the rest of the world, that these are druggable targets," said Glenn Kazo, chief business officer at Ariz. "Having some really good animal data that tells us the approach we're taking for targeting [PRDMs] is able to achieve the biological effect that we want is the reason we are coming out of stealth mode."
Along with the breast cancer study, Ariz has done in vitro studies showing the proof of principle in lung cancer, colon cancer, and myeloma. The company's focus for now is on its lung cancer candidate targeting PRDM2, which Kazo said is "the best example that also has commercial viability."
One clue that PRDM2 was a druggable target for lung cancer were studies that linked PRDM2 gene methylation to smoking based on an analysis of samples from patients with non-small cell lung cancer. In one such study, published in OncoTargets and Therapy in 2018, the researchers concluded that "smoking may be an important cause of PRDM2 and PRDM16 gene methylation in squamous cell carcinoma of the lung."
"That was the first hint toward whether PRDM2 may be misregulated in lung cancer," Kazo said. "Then that gave us a very large target market within a very large cancer type, giving us a great commercial opportunity."
The opportunity in PRDM-targeted cancer drugs is the ability to control what Kazo called a "master switch." Rather than developing drugs to target very specific alterations, Ariz believes its drug candidates could halt the initial epigenetic changes that make a cell cancerous.
Independent studies have also found that PRDMs could have potential in cancer diagnosis and treatment. A 2020 analysis published in the International Journal of Molecular Sciences concluded that the "current knowledge on the PRDM protein family functions […] strongly suggests a valuable potential in cancer management, including diagnosis, prognosis, and therapy."
That analysis looked at the role of PRDM genes in cancer. PRDMs are thought to control or regulate many genes associated with cancer, the researchers concluded. For instance, PRDM1 can bind to the TP53 promoter and repress its transcription, which plays a role in blood cancers, while PRDM16 inhibits epithelial mesenchymal transition (EMT) by repressing the transcription of MUC4, a gene often overexpressed in pancreatic, lung, and colon cancer, among others.
"We believe that these epigenetic changes [in PRDM genes] are the first initial changes that occur in the cancerization of the cell," Niles said. "Because we're targeting this genetic change, we're able to see the patients that have had this change occur and thus are able to select the patients that would best be able to respond to our particular type of treatments."
Ariz is planning for big moves in 2021 as the company begins to attract more attention. In 2020, Ariz was one of nine winners at Johnson and Johnson's QuickPitch competition at the 2020 JP Morgan Healthcare conference. At the 2020 BIO International Conference, Ariz was voted as the "Buzz of BIO" winner in the Technologies of Tomorrow category.
The biotech has also partnered with other pharma companies, Pennsylvania-based Keystone Nano and Indian firm Sphaera Pharma, to collaborate on studies and bring together Ariz's products with different drug delivery technologies. Ariz has partnered to pair its platform with Keystone's nanoparticle drug delivery technology, while Sphaera has helped Ariz conduct some preclinical studies, the company said.
Toward the end of 2020, Ariz secured $685,000 in seed financing in a funding round led by Moneta Ventures. This latest funding will go toward expanding the management team and advancing its PRDM-directed product candidates.
Specifically, in 2021, the company will put the raised funds toward animal studies for its lung cancer product, Niles said. Based on the results of these animal studies, Ariz plans to submit an investigational new drug (IND) application to the US Food and Drug Administration in the next year, which will enable human trials. In those trials, the company expects to focus on lung cancer patients with PRDM2 epigenetic changes. There are currently no genetic tests approved by the FDA that specifically examine PRDMs. Until a PRDM-specific test is approved, the standard is to use screenings that examine methylation, "an important event in regulation of the PRDMs," Niles explained.
"At the same time, we want to flesh out the other opportunities, to make sure the lab work is not limited just to the lung cancer side of things or just the RNA approaches," Kazo said. "We want to make sure we're understanding the PRDM family in its totality and identifying the opportunities that are there."
The company is also planning for a Series A funding round to continue building out its other products this year. The leaders said they don't want to be limited to a single asset and are hoping to raise more funds for other pipeline candidates.
Ariz also hopes its work, along with the previous research on PRDMs' role in cancer, can convince the drug industry to consider PRDMs for precision medicine, Kazo said.
"This is one of the first times that people in the drug industry and precision medicine have recognized that this this broad class is druggable," Kazo said. "That's been our goal to tell people it's really time to look at this again in that context and we're spending a lot of time educating people on PRDMs as viable candidates."