May 15, 2017, (Research Matters):
The world is increasingly seeking a miracle cure for cancer, a disease that is behind one in every six deaths globally. However, scientists and health professionals are convinced that there cannot be such a ‘one-drug-cures-all’ elixir since cancer is not a single disease, but a class of diseases. There are many things that could go wrong, many reasons why one random cell in our body could decide to abandon all norms and divide incessantly. The drug that worked for one may not work for the other since each cancer is different. A one-drug-cures-all concept, as far as cancer is concerned, is pretentious optimism at best.
In spite of this seeming pessimism, there are a number of therapeutic measures that have been successful in curing specific types of cancers. One recent practice is the use of targeted therapy. Targeted therapy, as the name suggests, involves the use of ‘designer molecules’ directed against a particular rogue molecule in the body that is responsible for cancer. Many such molecules have found phenomenal success as effective cancer drugs in recent years. The latest discovery from Prof. Sathees Raghavan’s group at the Department of Biochemistry, Indian Institute of Science, Bangalore, in collaboration with researchers from various other institutes, is a noteworthy addition to this list of molecules.
The researchers have designed and synthesised a new drug called ‘Disarib’ that can kill cancer cells overproducing a protein called BCL2. This molecule, the researchers claim, works better than the current best BCL2 inhibitor in the market, with a lot more promise.
The role of BCL2 in cancer
BCL2 is a regulator protein molecule found in our cells. Its primary job is to suppress a process called apoptosis– a method of programmed cell death. This suppression is important since we don’t want our cells to simply die. However, when our cells are diseased or worn out, then apoptosis becomes necessary.
In cases where apoptosis fails, when our body cannot get miscreant actively-dividing cells to commit suicide, that’s when the cells become pathogenic and turn cancerous. And BCL2, as an apoptosis inhibitor, helps them do just that. Hence, targeting BCL2 may be a clever idea to control the progression of cancer. “BCL2 is an attractive drug target because many different cancers, including a lot of chemo and radiotherapy resistant ones, over produce BCL2”, explains Prof. Raghavan. “The normal cells in our body, in contrast, make very less BCL2. Drugs designed to inhibit BCL2 thus affect only cancer cells and little else”, he adds.
Designing effective BCL2 inhibitors, however, is not that simple. There are a number of proteins in the BCL2 family of proteins that share a degree of structural similarity but differ in their functions. Because of this structural similarity, most inhibitors that target BCL2 invariably end up interacting with some of the other proteins, resulting in unwarranted side effects. For example, many such BCL2 inhibitors have been found to affect the platelets in our blood necessary for the clotting mechanism because other proteins in the BCL2 family govern the survival of platelets. “There have been several inhibitors of BCL2 that have been synthesised, among that few seemed to be doing well in its initial stages of trials. However, even though these molecules entered clinic trials, none of them was approved, since the side effects like low platelet counts could lead to a whole new set of complications inhibitors”, says Prof. Raghavan.
A good BCL2 inhibitor is, therefore, one that induces apoptosis in cancer cells, without causing a decline in the platelet count. So far, the Food and Drug Administration (FDA) of the US has only approved one BCL2 inhibitor last year –ABT199 – that can induce apoptosis in cancer cells without harming the platelets. However, it is not free of other side effects like decreased white blood cell counts, diarrhoea, anaemia and nausea and some more serious ones like pneumonia and tumour lysis syndrome.
Disarib – The new kid on the block
Disarib is the culmination of 8 years of collaborative research involving 24 researchers from 8 different research groups across various labs, including the Department of Biochemistry (Prof. Sathees C. Raghavan's group) and the Molecular Biophysics Unit (Prof. Avadhesha Surolia's group) at the Indian Institute of Science, Institute of Bioinformatics and Applied Biotechnology (Prof. N. Yathindra's group and Prof. Vibha Choudhary's group), Department of Pharmaceutical Chemistry, KLE University’s College of Pharmacy (Prof. Subhas Karki's group), all from Bangalore. In addition, there are contributions from the Department of Molecular and Clinical Cancer Medicine University of Liverpool (Dr. Nagesh Kalakonda's group), UK, Rajiv Gandhi Centre for Biotechnology (Prof. T. R. Santhosh Kumar's group), Trivandrum and Advanced Centre for Treatment, Research and Education in Cancer (Prof. Pritha Ray's group), Mumbai.
The molecule was synthesised at Prof. Subhas Karki's laboratory in KLE University's College of Pharmacy in Bangalore. Ms Supriya V. Vartak and Ms Divyaanka Iyer, graduate students with Prof. Raghavan, at the Department of Biochemistry, IISc have also contributed significantly to the study. The researchers have filed for an Indian patent and have also initiated the process of filing application for the Patent Cooperation Treaty which grants intellectual property protection in several countries around the globe.
But what is so impressive about Disarib? There are many. Firstly, it is one of the handful drug molecules that have been completely developed in India, right from conceptualization of a new idea to development to testing and trials –a rarity on its own! The drug molecule itself warrants its own fair share of attention because of its numerous merits. Disarib inhibits the action of BCL2 without damaging platelets, much like the ABT199. Its mode of action in causing apoptosis, unlike the ABT199, is a lot more specific, eliminating the possibility of a number of side effects.
In fact, results of the studies from Prof. Raghavan’s group show that Disarib performs better than ABT199 in eliminating cancer cells. It does so at a significantly smaller dose, further reducing the chances of unintended side effects. “Also, the smaller size of Disarib molecule, compared to ABT199, makes it easier for the drug to reach the cancerous cells where it can begin destroying the tumour says”, Ms. Supriya Vartak.
The researchers have left no stone unturned during the study on Disarib, including its mechanism of action. Following a number of preliminary testing and analyses, the drug was tested in cancer cell lines, animal models, patient samples and more. The team even successfully utilised a humanised model of tumour in mice for ovarian carcinoma, in addition to three independent mouse tumour models for investigating the tumour regression property of Disarib. The molecule was found effective against a range of cancers –leukaemia, lymphoma, breast cancer, ovarian cancer and colon cancer. “In all the cases, our molecule was performing better than the ABT199, which is why we decide to patent this molecule”, says Prof. Raghavan.
The road ahead for Disarib
Though the initial findings of the studies seem very promising, there is still a long way to go before we see Disarib on the shelves of a pharmacy. A number of pre-clinical trials are yet to be done before the drug even gets approved for clinical trials.
“There were a number of criticisms initially”, recollects Prof. Raghavan, “so we designed more experiments, brought in more experts and came up with more and more evidence to support our findings.” Of course, pharmaceutical giants in the west that have invested in such molecules would certainly not appreciate another molecule invading their proprietary space in the market. “Currently, however, some pharmaceutical companies have shown an interest in our molecule, which is very encouraging. Now we are working towards a bigger version of the study, bringing in more chemists and clinicians. It will be quite a while before we can decide whether it will hit the markets. However, it looks very promising”, he concludes, optimistically.