Irradiating mutant flies may sound like a decent premise for a new sci-fi movie, but Dr. Tin Tin Su is looking to put this approach to a more practical and potentially profitable use – the initial screening of cancer drugs. Su’s lab at CU Boulder focuses on using Drosophila (fruit flies) to understand how cells safeguard the genetic information in their DNA. The path from Su’s more general research to the idea behind her company, Suvica, focused on cancer drug screening, offers an interesting story.
The basis for Suvica came from the surprising results of an experiment in which drosophila larvae that were mutant for Grp were exposed to ionizing radiation (IR). To take a step back, Grp is the fruit fly equivalent of the human Checkpoint kinase 1(Chk1). In human cells, as the name suggests, Checkpoint kinase 1 serves at a point where a cell stops and checks to make sure its DNA is intact before proceeding through the cell cycle and cell division. Exposing cells to radiation creates significant DNA damage including double-stranded breaks. If a cell tried to divide with such damage, cell death is likely making it important for Chk1 to stop the process until the DNA can be repaired. Previous experiments have demonstrated that human cells lacking proper Chk1 function are more likely to die if exposed to IR than normal cells with similar results in drosophila cells mutant for Grp.
Su’s team sought to replicate these results but instead of using cells in a Petri dish they would use whole organisms, specifically Drosophila larvae. They exposed both mutant larvae and normal, or wild-type, larvae to IR and were surprised to find that the mutant larvae were no more likely to die than wild-type. What Su and her team did observe was that the mutant larvae ate significantly more before moving on to the pupa stage.
This observation generated the hypothesis that the absence of Chk1 was causing more cell death in the mutants, but the organism was compensating by producing more new cells leading to the increased nutritional needs. More generally, the thought was that organisms may have “compensatory mechanisms” that allow the organism as a whole to survive where individual cells would not. Su’s team confirmed this hypothesis through separate experiments which showed that if these compensatory mechanisms were limited by environmental factors (restricting nutrition), by genetic mutation (larvae also mutant for growth factor signaling), or through drugs (colchicine which blocks extra cell division) the mutant larvae did die more often than the wild type.
But how do these finding relate to cancer drug discovery? There are a couple of important things to know to understand the connection. First, a large proportion of cancerous solid tumors are deficient in checkpoints. Second, traditionally initial screens for cancer drugs are performed on cells with tumor specific mutations like Chk1, not whole organisms. As Su’s experiments demonstrated, it is a lot easier to kill tumor-like cells lacking Chk1 in a dish than it is to kill a system with the same deficiency. This fact means that a lot of drugs may seem effective when tested on tumor cells but when they move on to further screening in larger systems efficacy may be limited.
Su combined this knowledge to the idea of screening drugs in mutant Drosophila. In this screen, the drug is both tested in tumor like cells (lacking Chk1 function) and in a whole animal model that has compensatory mechanisms. According to Su, “the beauty of this screen is that you don’t have to know what’s important – the biology of the system tells you what’s important.” In a sense what Suvica is doing is “the opposite of the research that is being done on targeted therapies.” Where targeted therapy research focuses on the theory of identifying an important pathway and finding a molecule to inhibit it, Suvica’s approach rests on identifying a good model system and then testing as many molecules as possible in that system.
Su’s team has screened a library of 1990 molecules (of disparate chemical properties, some of which had proven cancer activity) for use in combination with radiotherapy on mutant Drosophila after exposure to IR. From this library, four drugs were found to be effective compared to the 1004 which cell-based assays would have sent on for further testing. Of these 4 molecules identified through the Drosophila screen, two have known anti-cancer activity and one, Topotecan, is currently in trials in combination with radiation for several types of cancer – the results of which (if positive) could help validate Suvica’s method. The other two molecules identified are not known anti-cancer agents presenting the opportunity of further development and commercialization. Su has partnered with researchers in the animal core at The University of Colorado Denver Anschutz Medical Campus to take the more potent of these molecules through testing in mouse xenographs with funds from an NIH grant.
The team has started screening through commercial libraries of molecules. Additionally, Suvica is in the process of securing patent protection for their method. Su is hoping for a broad patent that would cover use of Drosophila for cancer drug screening, as her team is interested in applying similar methods beyond combination with radiation therapy including testing for drugs that synergize with existing cancer medications and on mutants with common tumor mutations besides Chk1. Even if the patent granted is narrower, Su feels her team maintains an advantage because achieving reliable and repeatable results requires significant know-how related to raising Drosophila larvae. As Su puts it, “Someone couldn’t just go out and start one of these labs tomorrow.”
By Su’s admission, the business side is lagging a little behind the science which is why the team is currently seeking to add business leadership. If the current mouse studies prove successful, Su thinks the company would be in a good position to seek outside equity funding along with the SBIR and state grants that are currently being pursued. Due to Su’s expertise with Drosophila combined with the expertise of researchers at the animal core, the company’s best option may be to focus on screening molecules, bringing them through animal testing and then licensing them out prior to human trials, but the exact business plans are still evolving.
Su has big hopes for Suvica, believing the new screen to be a significant opportunity in truly identifying drugs that will synergize with other therapies – be it radiation or existing cancer medications. The benefits in finding these synergies would be in enabling lower dosing which in turn could lower side effects, while also potentially reducing the substantial cost of clinical trials by eliminating false positives early on. While there is still a long road ahead of Suvica in moving from the lab to product, the destination is hugely worthwhile: More effective cancer therapies borne on the gossamer wings of the tiny fruit fly.
