Advanced Cancer Therapeutics LLC

Advanced Cancer Therapeutics LLC is developing candidates against two cancer-metabolism targets. The first is PFKFB3, an enzyme that is believed to be a key player in glucose metabolism. Preclinical results suggest the compound inhibits tumors’ ability to consume glucose for growth and metastasis. ACT is also advancing a set of potential inhibitors against another key metabolic target called choline kinase, which is responsible for generating phosphocholine, one of the most important enzymes associated with choline metabolism and cell proliferation.

Blocking enzymes that help cancer cells grow

429 West Muhammad Ali Boulevard

Suite 600

Louisville, KY 40202

Phone: [phone]

Web Site: www. advancedcancertherapeutics.com

Contact: Randall Riggs, President & CEO

Industry Segment: Biotechnology

Business: Cancer therapeutics

Founded: January 2007

Founders: Dale J. Boden; Ty Wilburn; Donald Miller, MD, PhD

Employees: 3

Financing to Date: $10 million

Investors: University of Louisville; Private investors

Board of Directors: Dale J. Boden (BF Capital); Donald Miller (James Graham Brown Cancer Center, University of Louisville); Robert W. Rounsavall, III (Dixie Real Properties); Ty Wilburn (Merit Health Systems); James R. Ramsey (University of Louisville)

Scientific Advisory Board: Donald Miller

Companies intent on developing drugs to interfere with cancer metabolism are sharing few details of the molecular targets they are investigating – let alone the chemical compounds they hope will eventually become successful drugs. As the hunt for cancer metabolism targets heats up, commercial success in the area is more likely to hinge on compounds than targets, says Randall Riggs, the president and CEO of Advanced Cancer Therapeutics LLC (ACT). Like other young companies in the space, ACT was inspired by a key insight made by German biochemist Otto Warburg, MD, PhD, who observed that cancer cells have a large appetite for glucose, and if starved of it they go into apoptosis, or programmed cell death. Although scientists have been aware of the so-called Warburg effect ever since, the molecular mechanisms behind it are only now becoming known. The key papers in the field are only just emerging.

The hypothesis that blocking glucose uptake will prevent cancerous cells from proliferating has yet to be validated through human clinical trials. Increasingly, researchers are looking beyond glucose to other nutrients that cancer cells rely on to sustain themselves, and plotting ways to deprive cancer of these vital substances. In some ways, the mounting enthusiasm for cancer metabolism recalls the excitement over angiogenesis, the means by which solid tumors co-opt and build their own vasculature systems. Judah Folkman, MD, championed the phenomenon as an avenue to drug discovery in the 1980s, and lived to see ridicule of his idea shift to the sincerest form of flattery – its being embodied in valuable drugs like the blockbuster Avastin (bevacizumab). Researchers now suspect that cancer metabolism may yield drug targets even more fundamental to a wider range of cancers, including blood-borne cancers such as lymphoma and leukemia.

Before stepping into his current role in October 2007, Riggs was SVP of corporate development for BioCryst Pharmaceuticals, where he oversaw the negotiation and management of nearly $1 billion worth of strategic partnerships with multinational firms. Riggs previously held the same title at Lexicon Pharmaceuticals. He began his career in pharmaceutical sales at Eli Lilly before being promoted into business development positions there.

"People may try to claim that they own all the modulators that inhibit a given target, but relying on targets to gain exclusivity is probably not a good strategy," Riggs declares. He notes that when Pfizer Inc. tried to claim intellectual property rights not only to Viagra (sildenafil) but to all other inhibitors of the enzyme phosphodiesterase 5, "the court said no. Lilly's compound against the same target was deemed not to infringe Pfizer's IP," and Cialis (tadalafil) was allowed to go forward to market.

For its part, ACT is presently developing compounds against two cancer-metabolism targets. The first target is PFKFB3, the short name for an enzyme that is officially known as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and which is believed to be a key player in glucose metabolism. The initial "hit" compound ACT licensed from the University of Louisville's James Graham Brown Cancer Center in Louisville, KY, was called 3PO. [See Deal] Riggs says ACT has since identified over 125 potential inhibitors of PFKFB3 and has defined two distinct compound families. Through its partnership with the university, ACT has been able to demonstrate that many of these compounds targeting PFKFB3 exhibit anti-cancer effects in 12 cancer cell lines and five different animal models, Riggs asserts. He adds, "We've looked at both solid tumors and blood-based cancers, and we are seeing good enzyme inhibition with a candidate that already has approximately 40% oral bioavailability."

Like other executives in the field, Riggs points out that imaging technologies such as PET (positron emission tomography) can easily track the movement of glucose in tissue, and so provide evidence of a compound's ability to block uptake of glucose by tumor cells. In preclinical tests with a lead compound referred to as ACT-PFK-015, he recounts that PET scans given 30 minutes after the drug candidate was administered show tumors that were given placebo "lit up like a flashlight" due to glucose uptake into the tumor. Tumors treated with just one dose of ACT-PFK-015 and evaluated 30 minutes later did not light up, Riggs says, "which suggests the tumor's inability to consume glucose for growth and metastasis. It's very encouraging."

The start-up is also advancing another set of potential inhibitors against a different key metabolic enzyme called choline kinase (CK). This enzyme is responsible for generating phosphocholine, which Riggs explains is one of the most important enzymes associated with choline metabolism and cell proliferation. Because phosphocholine is commonly over-expressed in solid tumors, Riggs suggests it could be a biomarker to evaluate the effectiveness of a choline kinase inhibitor: "If you see a patient's phosphocholine levels go down, that would be an indicator that the drug is working." Already, Riggs says that several of the compounds ACT is investigating as potential CK inhibitors have demonstrated inhibition of cell proliferation among 13 cancer cell lines, inhibition of enzymatic activity against the recombinant protein of CK, and inhibition of tumor growth in xenograft studies.

Although ACT itself operates with only three employees, Riggs emphasizes that the company is fortunate to have established an innovative partnership with the James Graham Brown Cancer Center, which allows the start-up to work with many top-notch researchers focused in oncology. The partnership also brings ACT the opportunity to conduct Phase I human trials at the University of Louisville Hospital, which has previously carried out such studies for others.

While Riggs clearly prizes his company's connection to the University of Louisville and to Kentucky, he is also pleased to be working with a team of 11 medicinal chemists in Jaipur, India. Even now, he says, the group is working to improve ACT's inhibitory compounds, so the company can select just one to register and evaluate as an investigational new drug.

The medicinal chemistry team is one that Riggs worked with during his time at BioCryst. Beyond high-quality, trust and good value for the money, the relationship with a team of scientists in India also opens up the possibility that ACT will have access to cancer patients in India. Typically, regulators in India do not permit first Phase I human clinical trials to be conducted on its citizens by a foreign company, unless that drug has actually been invented or developed in collaboration with an Indian company.

Thanks to ACT's colleagues in Jaipur, Riggs notes, "Our drugs are being developed and invented there, and we could see ourselves taking advantage of that opportunity." In the US, companies testing potential cancer treatments in early clinical trials generally only have access to patients who have failed many other possible therapies. By contrast, in India, Riggs says that "most cancer patients will not have been heavily treated, if they have been treated at all." The situation could give ACT a clearer perspective on whether and how, and for whom, its drug candidates are effective.

Advanced Cancer Therapeutics has accepted no venture capital since its founding early in 2007, growing instead on $10 million raised entirely from the University of Louisville and private investors from Kentucky. [See Deal] "A lot of our investors have been personally affected by cancer in some way, and their heart is truly about bringing patients novel drugs that could cure or severely retard cancer growth," Riggs declares. Their orientation is decidedly different than that of traditional VCs "who might respond when they see a cool technology inside a company they think they can sell in three to five years."

Not only does ACT's financing come entirely from Kentucky, but so does its intellectual property portfolio – which already contains assets beyond those related to cancer metabolism as a hedge against risk. The University of Louisville Research Foundation owns 30% of the company, and under most conditions, ACT is granted an "initial option" on anything developed by approximately 50 scientists at the James Graham Brown Cancer Center. Riggs believes the arrangement offers ACT "better odds for success than a typical biotechnology start-up," and not only because the university invests approximately $30 million annually in cancer research.

Riggs believes ACT's business model benefits greatly from the University of Louisville's willingness to establish pre-set business terms for out-licensing assets to ACT, even before an asset is created. Scientists and institutions tend to balk at such a suggestion, he acknowledges, but the ownership share and ACT's development plans make clear that "if ACT succeeds, everybody wins." Whereas many companies may take as long as one to two years to conclude a licensing deal with an academic or medical institution, Riggs boasts that ACT can complete one in about two weeks – and set to work that much faster. ACT will only license intellectual property that is already backed up by in vivo data, Riggs emphasizes, "and I don't take anything unless I know the inventors are going to continue to be involved with development."

– Deborah Erickson