Highlights/Stories
Mark Cushman
Back in the 1970s, when Mark Cushman first began experimenting with the synthesis of natural products for cancer treatment, he serendipitously created a class of anti-leukemia agents called indenoisoquinolines. But when National Cancer Institute researchers concluded one of them was not as effective as other leukemia treatments, the compound was filed away and nearly forgotten.
Then 18 years later, Cushman received an unexpected call from an NCI researcher, who’d been running Cushman’s agent through a computer program that analyzed its effects against different kinds of cancer cells. “He was very excited and said that indenoisoquinoline had the same cytotoxicity profile as some clinically useful topoisomerase I inhibitors,” says Cushman, a distinguished professor of medicinal chemistry and a member of the Purdue Institute for Drug Discovery. “He wanted us to send more of the compound to test.”
Cushman and his team have been perfecting the anticancer activity of the lead indenoisoquinoline. After synthesizing 500 pounds, he provided two optimized compounds to NCI, where they’re being tested against colorectal and other cancers.
Already, results are promising; in one patient with metastasized colon cancer whose lung nodules had not responded to other treatments, physicians discovered a decrease in the size of nodules after just five days of Cushman’s agents.
“This is the first evidence of efficacy that we have seen. Other drugs were not working, but our drugs are, so that is good news,” Cushman says. “I’m thrilled to be involved in this type of research because it allows us to create organic compounds that don’t exist in the known universe — and won’t exist unless we put them there.”
Andrea Kasinski
In her laboratory in the Bindley Bioscience Center’s Multidisciplinary Cancer Research Facility, a sunlit environment where graduate assistants bustle between fluorescent imaging systems and injectable plate readers, Andrea Kasinski is laser-focused on two goals.
Her first goal: to better understand how cancer therapeutics work. “A lot of times we take a small-molecule drug and try it, but we don’t know why it works,” says Kasinski, the William and Patty Miller Assistant Professor of Biological Sciences and a member of the Purdue Institute for Drug Discovery. “I want to know what we are hitting and what the potential side effects are.”
Her second goal: to give people hope. “It’s always important to ground myself in the idea that our work can benefit someone,” she says.
Kasinski hopes to accomplish both goals while studying lung cancer, which kills more men and women than breast, colon and prostate cancers combined. When diagnosed while the cancer is still localized within the lung, the five-year survival rate is around 50 percent. But 85 percent of lung cancers are diagnosed after they’ve spread to other organs, and five-year survival rates among those patients is only 4 percent. That’s in large part because as the cancer metastasizes, it mutates into varieties often resistant to available drugs. Kasinski believes that microRNAs could hold the key to future treatments.
Discovered 21 years ago, these small, non-coding RNA molecules are now known to bind to certain genes even if they’re not perfectly complementary, so a single miRNA is theoretically capable of affecting several different genes that are causing cancer to grow. Around three years ago, Kasinski determined that restoration of a particular miRNA has a therapeutic effect on lung cancer in mice. Now she’s collaborating with clinicians and Mirna Therapeutics to study the miRNA in a handful of patients around the world. It’s the very first clinical trial for an miRNA.
For purposes of the trial, patients with liver cancer are being studied. “But if this works — and we’re optimistic — it will hopefully be useful in a variety of cancers, including lung,” Kasinksi says. Although Kasinski did her postdoctoral work at a university with its own hospital and where she could attend case conferences whenever she wanted, the fact that Purdue is a basic cancer research center hasn’t held her back at all. “I still work with many of the leading lung cancer physicians in the world,” she says. “And if anything, I think the environment at Purdue promotes our work. Basic science fuels clinical application. Otherwise, you’d be going through blindly and cherry picking.”
Debbie Knapp
Cancer steals loved ones away — not only our family members and friends but our companion animals, too. Dr. Debbie Knapp wants to save both as co-director of the Purdue University College of Veterinary Medicine’s Comparative Oncology Program.
“In my job, I get to help the dogs, help the dogs’ families and learn something that helps people,” says Knapp, the Dolores L. McCall Professor of Comparative Oncology and a member of the Purdue Institute for Drug Discovery. “That is a tremendously exciting thing to do.”
Consider, for instance, a particular kind of bladder cancer known as invasive transitional cell carcinoma (InvTCC), which kills more than 14,000 people and an estimated 20,000 dogs annually in the United States. Because canine and human versions of InvTCC have very similar cellular and molecular features, biologic behaviors, and responses to therapy, breakthroughs in treating pets with InvTCC could benefit humans as well.
Most deaths from InvTCC are caused by tumors that can’t be removed. One of the new drugs which could offer hope is tubulysin B, but only if it can destroy cancer cells without damaging healthy ones in the process.
Knapp and her team are collaborating with Phillip Low, Purdue’s Ralph C. Corley Distinguished Professor of Chemistry and director of the Purdue Institute for Drug Discovery, whose laboratory has pioneered the use of folate in targeted cancer treatment. Certain cancers can take up much more folate than normal cells, and folate can guide drugs into the cancer, while not harming other organs. Knapp’s team is evaluating tubulysin paired to folate in dogs with naturally occurring InvTCC to see if the drug will attack the tumors with sufficient force while leaving healthy cells intact.
“We want to determine ‘Does it work? Is it safe? And what dosages appear appropriate?’ to help guide the application in people,” says Knapp. As the work could set the stage for human clinical trials, Knapp hopes to extend the lives of beloved pets as well.
Philip Low
On Target Laboratories LLC and Purdue University are clinically investigating optical imaging technology that could "light up" cancer cells and help surgeons remove more cancerous tissue than previously possible during surgical procedures.
The technology was developed by Philip Low, the Ralph C. Corley Distinguished Professor of Chemistry at Purdue University, and co-founder of On Target Laboratories.
On Target Laboratories' lead molecule OTL38 achieved first-in-humans status at the Center for Human Drug Research, affiliated with Leiden University. It was the first time the compound was given to humans as part of testing. The clinical trial in healthy volunteers is complete and it demonstrated the safety of the molecule at various doses. The next step in development of this molecule will be the evaluation of efficacy and safety in patients with cancer.
"On Target Laboratories has developed small-molecule ligands, such as OTL38, that specifically target receptors over-expressed on solid tumors. We have attached them to proprietary fluorescent imaging agents that allow the cancers to light up during surgery," Low says. "We anticipate these tumor-targeted probes could help surgeons remove more of the tumor than would have been otherwise possible."
Data from the initial use of this technology in humans was published in Nature Medicine in October 2011. Low says the collaboration with Leiden University Medical Center will enable oncology surgeons to test the probes in surgeries for different cancers including breast cancer, lung cancer and ovarian cancer.
"My colleagues and I are very excited about this collaboration because it will help real-world translation of our technology for the management of this devastating disease,” Low says. “Surgery is pivotal for the treatment of most solid tumors, and our developing technology could, in the future, be the guiding light for surgeons by enabling intra-operative visualization of most such tumors."