came back from a conference of the American Association for Cancer Research
, wondering about a statement from one of the speakers. A cancer
patient, the speaker had said, would have to wait for a few months to know whether the prescribed drug is killing the cancer cells or not. If it is not, as is the case most of the time, the patient and the doctor would have wasted valuable time on an ineffective drug. "Why do we have to wait for several months," Kulkarni asked himself. "What can’t we figure it out immediately?
That was three years ago. The question was of immense significance to cancer treatment. Patients would have improved quality of life and better chances of survival if oncologists could figure out quickly the response of a tumour to a particular drug.
Kulkarni was then working as a post-doctoral researcher in the lab of Shiladitya Sengupta, principal investigator at the Brigham and Women’s Hospital in Harvard. He had several brainstorming sessions with Sengupta and RA Mashelkar, National Research Professor in India who was a visiting professor at Harvard University
at that time.Big breakthrough
Kulkarni, Sengupta and their colleagues have now found a method to watch cancer cells in the body die in real time, as a patient is treated with drugs. Their experiments on rats showed tumour cells light up in green as they die, within a few hours of giving the drug. The research was published on Tuesday in the Proceedings of the National Academy of Sciences, a leading journal. No one has been able to show such results even in the lab, and the consequences of translating this work to humans are huge.
"Predicting the drug response is the biggest issue we face," says Pankaj Bhargava, oncologist and senior consultant at the Dana Farber Cancer Institute in Harvard. "It takes two months and we would have treated the patient in a blind fashion." Bhargava was not involved in this research.
To catch cancer cells dying in real time, Sengupta’s lab members thought of a series of ingenious steps using ideas from nanoscience. They developed a small polymer that could be joined to a drug, and then joined drug-polymer combination with another molecule that would light up under certain conditions.
This drug-polymer-reporter complex would assemble itself into a nanoparticle, which is usually taken up preferentially by cancer cells. Once inside, the particle breaks down and the drug kills the cancer cells, if they are sensitive to it. It was a good way of targeting the drug to the tumour. But the real use was in the reporting. "They have made the nanoparticles multifunctional," says Mashelkar, "making them both deliver and report."
The reporter molecule can light up in the right environment. Inside the cancer cell, this environment is the presence of a molecule called caspace, which is produced by cancer cells when they die. So in a dying cancer cell the reporter molecule reacts with caspace and lights up while it remains unaffected in a cancer cell that does not respond to treatment.
Oncologists can watch this within eight hours of giving the drug. The research, however, was carried out on rats. The scientists are tweaking the procedure now for humans. "We need three to five years to do this in humans," says Kulkarni, who is now an instructor in medicine at Harvard Medical School.
In recent years, research has been promising cures to many types of cancers sometime in the near future. On the one hand, scientists are using genomic analysis to predict the response to a drug before treatment. These procedures are improving treatment outcomes around the world, as patients are being given drugs that suit their genetic make-up and the mutations that cause the tumour. But a drug response prediction can be even more powerful if there is a method to quickly decide whether a particular drug combination is working. It is here that Kulkarni’s work would help.
The excitement around the world in cancer research revolves around the emerging field of immunotherapy, which uses the body’s immune system to clean up the cancer cells. In normal circumstances, cancer cells avoid attacks from the immune system by setting up a molecular flag, which fools the immune system into believing that the cancer cells are not intruders. Researchers have now figured out how to remove some of these flags, called immune checkpoints.
One such checkpoint is called PD-1, and there are drugs that block this molecule and clear the way for the body’s immune system. In one of the most remarkable cases so far, former US president Jimmy Carter
was cured of the deadly melanoma that had spread around his body, even though he was 91 years old when he received the treatment.
Companies are developing drugs against several other checkpoints around the world, but the treatment method is still bogged down by lack of a technique to quickly see what is happening to the tumour.
It is not often that a single immunotherapy drug works against a specific tumour. Oncologists use the drugs in combination, but combinations are more toxic to the body. Cancer cells respond differently to immunotherapy compared with chemotherapy.
Existing methods of drug response monitoring use the size of the tumour as an input to figure out whether the treatment is working. In immunotherapy, the tumour often grows in size before shrinking. "We need to separate real progression from pseudoprogression," says David McDermott, oncologist and associate professor of medicine at the Harvard Medical School.Powerful method
The Sengupta-Kulkarni research provides exactly that method, according to McDermott. "They seem to have improved the delivery system for both chemotherapy and immunotherapy," says McDermott. Since combination therapy is toxic, doctors need to figure out who needs more than one drug and who does not. Kulkarni and his team now provides a method. Once the technique works on humans, doctors may have with them a powerful way to attack cancer with both force and finesse.
Kulkarni and Sengupta have used molecules that are found in the body and thus not toxic. But the lighting-up method may not suit humans, and so they are looking at other options that could work. "It is a platform technology that can work with all drugs," says Mashelkar.
All the research team members, except one, are of Indian origin, and grew up and did at least part of their education in India. Kulkarni was born in a village in Maharashtra, did his schooling in Marathi, and studied chemical engineering at the Institute of Chemical Technology in Mumbai. The researchers used no fancy equipment. It was purely a matter of ideas.