Researchers use supercomputers, biology, drugs, surgical advances, and the body itself in an intricate approach to uncover which might hold the keys to curing cancer.
Cancer patients often feel as though they’ve walked through a forbidden door that has slammed and locked behind them. Diagnosis brings questions, fears, and treatments that may be as uncomfortable as the illness. Coming out on the other side to the freedom of good health is a journey that may take years, but novel approaches are bringing hope to patients battling many types of cancers.
For researchers at Purdue, the game plan for cancer isn’t finding one master key but cutting many and in some cases altering the tumblers in the locks themselves, changing the very nature of the disease. Timothy L. Ratliff, Distinguished Professor of Comparative Pathobiology and the Robert Wallace Miller Director of Purdue’s Center for Cancer Research, says a cure will come not from one eureka moment, but several, over time. “Cancer is a multi-faceted disease and that’s part of what makes it so difficult,” Ratliff explains. “There are just many, many forms that we have to find the tools to treat effectively.”
At Light Speed
Sometimes the best place to begin is at the beginning.
Nadia Atallah (A’11, HHS’ 11, PhD A’15), a bioinformatician in the Purdue Center for Cancer Research, works with Ratliff to study cancer at the molecular level. Ratliff, Atallah, and their colleagues are using genome analysis to study cancer at its most basic level, essentially creating maps of cancer cells and then determining which parts are essential for the disease to spread. Remove or alter a necessary component, and the cancer cell collapses. It also may be possible to examine the biochemical pathways of certain parts of cancer cells and design drugs that interact with them in a way that neutralizes the threat. Researchers could even predict how the pieces become malignant in the first place.
Ratliff and Atallah have been studying how one particular enzyme, SULT2B1b, relates to prostate cancer. Removing the enzyme in prostate cancer cells helps them compare whether genes are more or less active in the cells from which the enzyme has been removed versus those with normal levels of SULT2B1b. Isolating which genes are tied to the enzyme could help unlock new treatments and preventatives.
Purdue’s supercomputers, which regularly rank among the best in the nation, make it possible to run programs much faster than ever before. “To map all sequence reads for the SULT2B1b project to the human genome for one cell takes about 4.4 minutes on the super computer Conte,” says Atallah. “It would take over two and a half hours on a custom-made MacBook Pro. For a project with 550 cells, it takes about 1.7 days on Conte, whereas on a MacBook it would take 56 days.”
For Atallah, who went into cancer bioinformatics to tackle purpose-driven research, the ability to examine, compare, and share massive amounts of data quickly cannot be underestimated.
“With advances in technology, we also are able to look at genome architecture and activity at single-cell resolution,” she says. “This will help us gain a better understanding of how tumors evolve, what leads to metastasis, and also will enable us to move precision medicine forward, allowing us to cater more toward individuals when preventing against and treating cancer.”
A Fundamental Fight
Chang-Deng Hu is fighting cancer on that single-cell level. His research focuses on fundamental biology, which outlines how cells function under normal physiological conditions, and helps identify which genes and proteins within healthy cells may contribute to cancer development, progression, and therapy response.
The professor of medicinal chemistry and molecular pharmacology in the College of Pharmacy also has high hopes that his lab, by determining which parts of a cell mutate into cancers and why, can contribute to earlier diagnosis. He feels this is the true key to curing many forms of cancer. “We can cure cancers if we discover them earlier,” Hu says. “One example is that 99 percent of patients with localized prostate cancer can survive ten years whereas only 30 to 40 percent of patients with metastatic prostate cancer can survive ten years.”
Hu and his team also are studying how cancer cells react to drugs and how cancer itself may change during treatment. Hu has found that the biology of some prostate cancer cells actually shifts during radiation treatment to neuroendocrine cells, with the physical and biochemical genetics of the cell morphing into a different state. This metamorphosis is believed to contribute to radiation resistance and the recurrence of prostate tumors.
“We are trying to understand how this occurs at the molecular level so we may develop novel treatments to sensitize prostate cancer cells to radiation by preventing this change from happening,” Hu explains. Currently, traditional radiation and chemotherapy harm healthy tissue along with the diseased, resulting in side effects like nausea, hair loss, and fatigue. Finding markers on cancer cells that allow therapeutics to better hit their targets could reduce side effects, significantly altering how cancers are treated and how patients respond to treatment. “It is not a simple task, and perhaps impossible,” Hu says. “To just use basic biology to design drugs with high efficacy.”
Yet, right on the Purdue campus, it’s happening. Philip Low, director of the Purdue Institute for Drug Discovery and Ralph C. Corley Distinguished Professor of Chemistry, is currently at work on what he calls “smart bombs.” These potent therapies are crafted to deliver their doses of cancer-destroying drugs only to the cancer cells they are meant to eradicate. They are designed to attack illness with a laser focus rather than with a “spray and pray” strategy that has multiple side effects. Low likens the approach to the sorting toys with which toddlers play.
“We look at a cancer cell as that sorting ball,” Low says. “We want to push the uniquely shaped objects only through the complementary holes in the ball that they fit. We try to find a shape that’s present only on the cancer cell and not the healthy cell. Once we find that shape, we can dock it specifically to the cancer cell, delivering the drug only to that malignant cell.”
Most of the time, these shapes do not naturally exist. Low’s team will look for a marker on a cancer cell and design a molecule that is optimized to precisely deliver one of his powerful drugs. The molecules are tumor-specific, so one size does not fit all. “We are cutting the keys to open the lock that the cancer cell makes to protect itself,” says Low, noting that the process is now in human trials, but there is more work to be done. “The one that we’ve started off with works on 90 percent of ovarian cancers and 90 percent of lung cancers but only 10 percent of prostate cancers.”
Another approach that shows great promise is using chemistry and engineering to assist the body in killing cancer itself. Immunotherapy focuses on retraining the body’s own immune system to kill cancerous cells. Low’s team is combining the same science behind the homing molecules they have created to deliver drugs to cancer cells to direct a patient’s own killer T cells (one of the major cells in the body that kill foreign viruses) to destroy the cancer. Tumors naturally turn off the immune system in a mass. Low’s team removes T cells from a subject, genetically engineers them to target cancer cells by placing the homing molecules on their surfaces, and puts them back in the subject.
“These cells can recognize any mutation in the cancer cells,” he says. “They can even kill cancers that our drugs can’t touch. We’ve got it working beautifully in animals but we’re not in humans yet. We’re working as fast as we can.” Low predicts that the Food and Drug Administration (FDA) may approve the approach for human trials within a year but cautions that some issues must first be addressed before this type of immunotherapy can progress. Other types of targeted-cell immunotherapy have shown positive results, and he believes several of his modifications may improve on this success.
Veterinary Science Crosses Over
The science of human trials — how they are approved, created, and carried out — involves almost as many variables as there are types of cancers.
Improving these trials is a science of its own. One thing that could positively influence the arc of human cancer trials is man’s best friend — the dog — as well as the veterinary researchers who care for him.
Currently as few as one in 10 human cancer trials are successful because traditional laboratory studies do not provide sufficient information to know which drugs will truly benefit humans, says Debbie Knapp (MS V’88), the Delores L. McCall Professor of Comparative Oncology in Veterinary Clinical Sciences.
Certain cancers that naturally occur in dogs closely resemble their human counterparts, from the pathology and similarity of the tumors to the biological behaviors associated with how such cancers spread throughout the body. Urinary bladder cancer is one of those, particularly the most serious form of bladder cancer, invasive urothelial carcinoma (often called invasive transitional cell carcinoma or TCC). Knapp’s laboratory is studying the environmental and genetic risk factors for TCC in dogs, methods to detect it sooner, and approaches to more effectively treat it. A finding made between Knapp’s lab and Elaine Ostrander’s lab at the National Human Genome Research Institute reveals that canine TCC has a precise mutation thought to contribute to the cause of 8 percent of all human cancer across many cancer types.
Knapp’s lab is studying the effects of medicines that target the mutation, called BRAFV600E, in dogs. “By collecting small samples of the tumor tissue (via fiber optic scope) before and during treatment, we can analyze which molecular pathways are turned on or turned off during treatment, which of these are responsible for a favorable outlook, and which ones could predict resistance to medicines,” Knapp says.
Research with pet dogs can influence and improve the odds of therapeutics as well as cancer prevention studies in humans. “With the compressed life span in dogs, a cancer prevention study that would require 15 years in humans could be completed in two to three years in dogs,” she says. “Using dog studies to select the most promising approach in humans will save time, countless lives, and millions of dollars in cancer prevention studies.”
Better Surgeries, Better Outcomes
While prevention and drug therapies are key to cancer treatment, Low points out that surgically removing all of the diseased tissue often still represents a patient’s best chance at survival. “If you cut it all out, you’ve won the battle,” says Low. “We’ve designed tumor-targeted fluorescent dyes that cause cancer tissue to grow brightly and leave healthy tissue dark. It greatly facilitates the ability of surgeons to find and cut out the malignant lesions, as opposed to the current situation where they look almost identical to healthy tissue.”
The simple injection of fluorescent dyes greatly improves the prognosis for most patients, but particularly those with hard-to-spot cancers such an non-small-cell lung cancer, where some 90 percent of patients die because surgeons cannot locate all of the disease. Ovarian cancer patients, with a 50 percent survival rate for the same reason, also experience improved prognoses.
Doctors remove all of the diseased cells they can see during surgery, then turn on fluorescent lights to remove the rest of what glows. Phase two of human clinical trials, which involved 45 patients, is complete. New treatments must pass three phases of human trials before final approval for the general public by the FDA. The final phase for the glowing cell treatment will include 100 patients, and Low says the FDA plans to fast-track approvals based on positive results.
“We have to show that all the fluorescent lesions are cancer,” he says. “We don’t want them taking out the good stuff. The pathologists are sent the removed lesion to say whether it’s cancer. But it’s very, very promising so far.”
Another Purdue discovery, currently in human trials at Indiana University Hospital in Indianapolis, Indiana, also focuses on improving surgical outcomes. The advanced imaging approach known as the MarginPAT system has the potential to lower the risks of reoperation in some of the 160,000 annually diagnosed breast cancer cases where patients are treated with lumpectomies.
Ji-Xin Cheng, professor of biomedical engineering and chemistry and the scientific director of label-free imaging at Discovery Park, co-founded Vibronix Inc., the company commercializing the system. The MarginPAT provides 3D cancer imaging by sending a laser pulse and an ultrasound pulse through a tumor or samples removed by surgeons during lumpectomies. Doctors are able to see a 3D image of the tumor material on a specimen after a four-to-five-minute scan. While still in the surgical suite, they can use it to locate tumor residue in the surgical cavity and remove all of the breast tumor tissue, eliminating the need for reoperation, which currently occurs in 20 to 70 percent of these types of surgeries.
“Total removal of the breast is still popular because people are worried about whether doctors are getting it all,” Cheng says. “Our device will ensure doctors remove the tumor completely while keeping the healthy part of the breast.” A new grant received by Cheng and his colleagues in September 2016 from the National Institutes of Health will help the company move toward the next stage of human trials and FDA approval.
Full Speed Ahead
The many facets and the depth of research happening in the field of cancer discovery and treatment are energizing to Ratliff, director of Purdue’s Center for Cancer Research.
“We will be curing some forms of cancer in 25 or so years,” Ratliff believes. “In 50 years, we’ll have many types of cancer under control. Where it took years to get the first full sequence of the human genome, we can do it in a few hours now. We can define your cancer very rapidly. We can understand the cancers much better. The technologies are catching up to our will. Times are ripe to make major discoveries and novel and effective therapeutics.”