There will soon be a ray of hope for cancer patients who fail to respond to conventional treatment. Researchers in the US, led by the India-born Rakesh Kumar, have stumbled upon a new way to keep rogue cells in check. But it will be years before clinical trials based on this breakthrough at the George Washington University Medical Center in Washington start.
Kumars team, which includes a scientist from the Rajiv Gandhi Centre for Biotechnology (RGCB) in Thiruvananthapuram, has been able to find the substance that disrupts mechanisms in normal cells, turning them cancerous. Their work, recently reported in the journal Proceedings of National Academy of Sciences, throws light on the workings of a protein — called metastatic tumour antigen-1 or MTA1 — that is associated with aggressive forms of cancer, including breast cancer.
This molecular insight into MTA1 could make it a target for developing new cancer drugs. Since the loss of MTA1 is not lethal as shown by our earlier work, it is now possible to develop strategies to target MTA1 in cancer cells to inhibit their growth, says Kumar.
Cancer has always intrigued scientists. The way the disease hijacks the machinery that a normal cell uses to grow and protect itself to take over that cell is baffling. No one puts it better than the Pulitzer-prize-winning doctor turned author Siddartha Mukherjee. Cancer is such a phenomenally successful invader and coloniser in part because it exploits the very feature that make us successful as a species or an organism, he says in his insightful tome, Emperor of All Maladies.
This line of enquiry has paid rich dividends in the past. Most anticancer drugs in the market today target a protein called p53, a substance that has crossed over from being an angel guardian of the cell. Researchers have seen that the p53 protein, which normally protects a cell, mutates in the majority of human cancers into a substance that in fact accelerates tumour growth.
While drugs that target p53 have been an important milestone in the fight against cancer, cancer biologists realised that not all patients respond to such drugs. This prompted them to look for other drug targets.
When Kumar, who moved to the US in 1984 after a PhD in biochemistry from the All India Institute of Medical Sciences in New Delhi, plunged into the challenging field of cancer research in the mid-1990s, he decided to focus on how cancer cells move and invade other areas. After all, cancer often kills when tumours invade new tissues.
Kumar noticed the protein MTA1 for the first time in 2002. He was trying to understand why many breast cancer patients do not respond to standard therapies. Their subsequent research found that at least one type of MTA1 protein may be playing a role in rendering common anti-breast cancer drugs like tamoxifen ineffective.
Further research showed that MTA1 is a central player involved in several cancer development signalling pathways. One such previously known mechanism is through a tumour suppressing protein called Alternative Reading Frame (ARF). In a normal cell, the ARF protein directs p53 to be active and stop all cancer-mutating events from accumulating. Hence ARF has a crucial role in keeping cells healthy and protecting them from an invading cancer.
The latest work, however, shows that MTA1 and ARF have an intriguing relationship. When the level of MTA1 in a cell exceeds normal, MTA1 itself alerts ARF, which swings into action to curtail MTA1 levels. This is despite MTA1 being a hyperactive tumour-triggering gene. Evolution seems to have installed a fail-safe mechanism to ensure the living cells remain normal, Kumar told KnowHow.
But the problem occurs when the ARF levels in a cell have dwindled. It is seen that ARF is functionally inactivated in about 30 per cent of cancer cases. This leads to an increase in MTA1 levels, increasing the cancer potential of a cell.
Since ARF keeps the MTA1 level inhibited in a normal cell, any loss or inactivation of ARF in tumour cells is likely to allow MTA1 levels to rise and consequently transform the cells, observes Kumar.
Another important finding is that MTA1 does not work through p53 and hence targeting p53 will not be of any help, when MTA1 levels high.
The work is significant because it identifies a new drug target in MTA1, says M. Radhakrishna Pillai, director of RGCB, who collaborated with Kumar on this study. Kumar has recently taken up an adjunct academic position as visiting distinguished professor at RGCB.
Kakoli Bose, a scientist at the Advanced Centre for Treatment, Research and Education in Cancer in Mumbai, seems to agree with Pillai. This study has not only opened a new avenue to look at MTA1 and its role in carcinogenesis (cancer initiation) and metastasis from a different viewpoint but has also shown promise to devise therapeutic strategies against cancer in future, she says.
In the man versus cancer fight, that is another point in mans favour.