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|NEWS IN BRIEF
|Year : 2019 | Volume
| Issue : 1 | Page : 93-95
|Date of Web Publication||4-Apr-2019|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
. News. Indian J Cancer 2019;56:93-5
Cancer therapy by “inhibition of negative immune regulation” awarded the 2018 Nobel Prize for Medicine
Although immunotherapy has been in use for the past eight years it received the Nobel Prize committee's attention in 2018 when the Nobel Prize in Physiology or Medicine was announced jointly to James P. Allison, PhD, The University of Texas MD Anderson Cancer Center, and Dr. Tasuku Honjo, Kyoto University, Japan on 1st October 2018. The researchers received total prize money of 1.1 million US dollars. Both these researchers had worked independently, at distant places, at different times, and studied different molecules but succeeded in developing drugs of the same class, albeit with different mechanisms of action. Although the research initially was not aimed at cancer, it has turned out to be a revolutionary advance in cancer therapy.
In an interview in 2015, after receiving the Lasker award, Allison spoke about how cancer affected his mother who died of lymphoma, two maternal uncles who died of lung cancer and melanoma, and his elder brother who had died from metastatic prostate cancer. He also shared that he and his another brother had undergone treatment for early prostate cancer.
CTLA-4 (cytotoxic T-lymphocyte associated protein 4), was first isolated and cloned in the late 1980s. Allison and colleagues, in 1994, at Berkeley University discovered that CTLA-4 negatively regulated T-cell activation. Subsequently, he explored the mechanism to enhance its expression, to treat autoimmune diseases. He did not think of utilizing it to treat a cancer, which employs exactly the opposite phenomenon. Later a new idea occurred to him, and he pursued the research to find a cure for cancer, by blocking the negative control of CTLA-4, thereby unbridling a full-fledged immune response. In 1996, he successfully demonstrated that antibodies against CTLA-4 not only made the tumors vanish from mice, but also prevented new tumor formation. While looking for a big company to test and promote this product he was told that it may have worked in mice, but it would never work in people. In 1999 he developed the first anti-CTLA-4 monoclonal antibody, Ipilimumab which acts as a “brake” or checkpoint inhibitor by preventing T-cell activation. In 2003, Ipilimumab was first tested in metastatic melanoma in humans. It took another 8 years, and another important clinical study in 2010, to persuade the health authorities about its utility and to receive FDA approval in 2011.
A couple of years before Allison's discovery, across the Pacific, Honjo and his colleagues were looking at another T-cell surface protein called PD-1 (programmed death-1), which they had isolated and cloned in 1992. Over the next 10 years, Honjo's group discovered that, like CTLA-4, it was also a checkpoint protein that acted as a 'brake' but operated by a different mechanism. Alongside, they were also attempting to find the ligand that binds with the protein PD-1. Together with Gordon Freeman at Harvard Medical School, they identified the associated ligand, PD-L1. Freeman and others discovered that some tumors may use PD-L1 to switch off the anti-tumor response in T-cells. They were the first to do so. As reported by the journal 'Nature', Freeman felt disappointed for not being selected by the Nobel Committee.
The Nobel Prize was awarded to the two, along with the winners in the other categories in Stockholm, Sweden on December 10, 2018.
HS Darling, New Delhi
Universal genetic testing for breast cancer recommended by Breast Cancer Network (BCN)
All breast cancer patients should undergo to genetic testing to guide their breast cancer care, and screening for other potential cancers. This is the recommendation of TME Breast Care Network (a group of 300 leading breast care physicians and researchers across USA) and Invitae (a genetic information company based in San Francisco, California) in a study presented at San Antonio Breast Cancer Society meeting and later, published in the Journal of Clinical Oncology on 7th December 2018. It recommends testing of a panel of 80 genes in contrast to the existing guidelines, where 11 genes are being tested.
Nearly 10% of breast and ovarian cancers are hereditary, most commonly due to BRCA1/BRCA2 gene mutation. Out of 1,000 breast cancer patients enrolled in this study, 50% met the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing (which relies heavily on BRCA1/BRCA2/PTEN and p53) and half did not. The difference in percentage of patients having pathogenic/likely pathogenic (P/LP) variants of those conforming to NCCN guidelines and those not complying was not significant. Hence, there is a need to broaden guidelines to incorporate additional genes to identify other possibly harmful mutations that could impact breast cancer management. Universal genetic testing (UGT) could also help relatives of a mutation carrier understand their cancer risk by undergoing cascade testing. The major dilemma of UGT is between the right to gain access to medical records of relatives in order to ascertain accurate cancer risk for a given family member and the right to privacy. Other considerations are the ethical issues of informing risk status to relatives if they have not actively sought it and the current high costs.
Dr Aparna Dhar (lead medical geneticist and genetic counsellor at CORE Diagnostics, Gurugram, India) explained, “Knowing genetic mutation tells us about the behavior of the cancer and the possibility of treatment with targeted therapies. The NCCN guidelines may not adequately reflect the evolving genetic knowledge, we might miss patients who should undergo increased cancer screening or potentially receive different systemic therapy.” Hence according to her, there was a need to broaden the testing criteria. She further added that we should ensure that patients and their families are explained about the risks and benefits of genetic testing to make better choice for themselves. She however, cautioned that the more genes we analyze, the more likely we are to identify variants of uncertain significance (VUS). Explaining meaning of VUS to patients would require professionals trained in their interpretation.
This study highlighted that current guidelines miss half of the patients with breast cancer with germ line mutations, thereby emphasizing the need for universalization of genetic testing of all breast cancer patients and not just those with an established family history.
“Permanent cancer cell sleep inducers” - the next big cancer treatment strategy?
In a discovery that could revolutionize cancer treatment, Australian scientists Tim Thomas and Anne Voss from the Walter and Eliza Hall Institute (WEHI) [Figure 1], Professor Jonathan Baell from the Monash Institute of Pharmaceutical Sciences and Dr Brendon Monahan from Cancers Therapeutics CRC have discovered drugs that specifically target cancer cells and could replace chemotherapy and radiotherapy in future for a number of cancers as they do not affect healthy tissues. The article first published in Nature in August 2018 was followed by detailed update on the official website of WEHI in November 2018.
|Figure 1: Associate Professor Tim Thomas and Associate Professor Anne Voss from the Walter and Eliza Hall Institute|
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KAT6A and KAT6B are lysine acetyltransferases, responsible for acetylation of histone proteins and for organization and function of chromatin. KAT6A is located on chromosome 8 and KAT6B on chromosome 10. Recurrent translocations in KAT6A (MOZ) and KAT6B (MORF) have been implicated in hematopoietic malignancies like acute myeloid leukemias, lymphomas and solid tumors like hepatocellular carcinoma, breast cancer, ovarian cancer, uterine cervical carcinoma, lung adenocarcinoma, colon and rectal adenocarcinomas, medulloblastomas and retroperitoneal leiomyomas. The team had discovered that survival of mice with MYC- induced lymphoma increase D four-fold when one of the alleles of KAT6A is lost. The above discoveries suggested that KAT6A and KAT6B inhibition could be a strategy for cancer treatment and were the basis for this research.
The drugs discovered, named as WM-8014 and WM-1119 [Figure 2]a and [Figure 2]b respectively] selectively target KAT6A and KAT6B respectively. They are reversible competitors of acetyl co-enzyme A and inhibit KAT6A/6B mediated acetylation of histones. Dr. Voss explained that the drugs “cause cell cycle exit by switching off their ability to trigger the start of cell cycle” causing senescence of cancer cells [Figure 3]. They induce “permanent sleep” of cancer cells without damaging their DNA or killing them. WM-8014 has shown to be effective in zebrafish hepatocellular carcinoma and in vitro while WM-1119 has been shown to be effective in lymphoma in mice.
|Figure 2: (a) Molecular structure of WM-8014. (b) Molecular structure of WM -1119|
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|Figure 3: WEHI.TV image showing the new drug (red) interacting with the target proteins inside a cancer cell. Created by biomedical animator Ms Etsuko Uno from the Walter and Eliza Hall Institute|
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In an email exchange, Dr. Richard Piekarz, MD, PhD, (Medical Officer in the Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute), stated that it would be worthwhile to evaluate these drugs for hematologic malignancies like leukemias and lymphomas after some pre-clinical work. He further added, “There seems to be some level of alteration in certain other solid tumors, but I don't know what the incidence is, and if targeting KAT6 would be effective.” He further stated that “Thanks to advanced molecular techniques, newer information has identified specific proteins in the epigenetic pathway which are either mutated or altered in specific cancers, and these are being targeted.” He also shared that NCI has also supported similar approaches as in the above study targeting newer targets which are considered 'epigenetic' targets.
Dr. Piekarz added that several FDA approved agents which target the epigenetic pathway - the DNA methyltransferase inhibitor and histone deacetylase inhibitors have been researched by the group including researchers such as Anita Roberts and Michael Sporn, Susan Bates and Tito Fojo and have led to several clinical trials and contributed to the FDA approval for some of the epigenetic agents. He also shared that drug companies are also developing agents against newer epigenetic targets that include EZH2 or the bromodomain proteins.
The most promising thing about these discoveries is that these drugs do not cause any collateral damage to healthy cells and are the first drugs to target the KAT6 system which was previously thought not to be amenable to any drug therapy. Though the KAT6A and KAT6B inhibitors are yet to be available for use in human beings, this research could pave an altogether different road for cancer treatment and prevention of recurrence.
Neha Chauhan, Bangalore
[Figure 1], [Figure 2], [Figure 3]