BOSTON — New clinical research shows that lamivudine, a reverse transcriptase inhibitor widely used in HIV therapy, stopped disease progression in 25% of patients with fourth-line metastatic colorectal cancer. Findings from the trial, published in Cancer Discovery, raise the possibility of an unexpected promising direction in cancer treatment, not just colorectal cancer.
The trial included 32 patients with advanced metastatic colon cancer whose disease progressed despite four lines of previous cancer treatments. The first nine patients received the standard HIV-approved dose of lamivudine. “After giving them only this one drug – nothing else – we saw signs of disease stability,” says co-senior author David T. Ting, MD, of the Mass General Cancer Center. After adjusting the dosing four-fold, another 23 patients received lamivudine therapy where it was highly tolerated.
The research team observed that 9 of the 32 patients, or 28%, had disease stability or mixed response at the end of the trial. “This provides evidence that an HIV drug can be repurposed as an anti-cancer therapy in metastatic cancer patients,” says Ting. While the research team did not see tumor shrinkage, the results are encouraging.
“If we see this kind of response with just one HIV drug, the next obvious trial is to see what else we can achieve with HAART, or highly active anti-retroviral therapy,” adds Ting, referring to the standard three-drug regime for HIV treatment.
The first clues to this unusual drug trial surfaced in Ting’s lab and those of his collaborators over the past ten years. The team discovered that up to 50% of a tumor’s DNA was composed of “repetitive elements”, which were previously considered “junk DNA”. “Only cancer cells produced these repetitive element, not healthy cells,” says Ting. Colorectal cancers produce abundant amounts of repetitive elements, as do cancers of the esophagus, lung, and several others. These repetitive elements spew out extraordinary levels of RNA which replicate in a viral-like life cycle through reverse transcription into what Ting describes at the repeatome.
The repeatome acts much like a virus does relying on reverse transcription to replicate itself and move in the genome. “It’s a way for cancers to change their genome to adapt to stress,” adds Ting, who had the idea to assess whether an HIV drug, lamivudine, might interfere with the process.
In their preclinical studies, Ting found that colorectal cancer cells were sensitive to lamivudine, reducing their ability to move. The team also discovered that the drug induced DNA damage and interferon responses, an indication that the drug triggered an inflammatory response in the tumor cells. Although not proven or evaluated in this trial, Ting theorizes that pairing reverse transcriptase inhibitor therapy with immunotherapy might encourage immune cells to become involved in these cancers.
Research shows that in a U.S. population of HIV patients receiving three-drug anti-retroviral therapy for life, their incidence of colon, breast, and prostate cancer was significantly less than the general population. Ting speculates this kind of therapy might prevent a cancer or a recurrence or turn a crushing metastatic disease into a chronic disease like HIV.
“We did the trial to see if we could learn something new about the biology of cancer cells and in the process found this unexpected, very encouraging result,” says Ting. “Disease stability in a cancer patient population this advanced, with just one single agent, is highly unusual and we are hoping we can soon initiate a larger Phase III study with a three-drug reverse transcriptase inhibitor combination.”
This work was supported with grants from the National Institutes of Health, Gateway for Cancer Research, Stand Up To Cancer (SU2C), National Science Foundation, Burroughs Wellcome Fund, V Foundation for Cancer Research, Affymetrix, Inc., ACD-Biotechne, Robert L. Fine Cancer Research Foundation, and the Pershing Square Sohn Prize—Mark Foundation Fellowship.
Other authors of the study include Mihir Rajurkar, Aparna R. Parikh, Alexander Solovyov, Eunae You, Anupriya S.Kulkarni, Chong Chu, Katherine H. Xu, Christopher Jaicks, Martin S. Taylor, Connie Wu, Katherine A. Alexander, Charly R. Good, Annamaria Szabolcs, Stefanie Gerstberger, Antuan V. Tran, Nova Xu, Richard Y. Ebright, Emily E. Van Seventer, Kevin D. Vo, Eric C. Tai, Chenyue Lu, Jasmin Joseph-Chazan, Michael J. Raabe, Linda T. Nieman, Niyati Desai, Kshitij S. Arora, Matteo Ligorio, Vishal Thapar, Limor Cohen, Padric M. Garden,
Yasmeen Senussi, Hui Zheng, Jill N. Allen, Lawrence S. Blaszkowsky, Jeffrey W. Clark, Lipika Goyal, Jennifer Y. Wo, David P. Ryan, Ryan B. Corcoran, Vikram Deshpande, Miguel N. Rivera, Martin J. Aryee, Theodore S. Hong, Shelley L. Berger, David R. Walt, Kathleen H. Burns, Peter J. Park, and Benjamin D. Greenbaum.
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2021, Mass General was named #5 in the U.S. News & World Report list of “America’s Best Hospitals.” MGH is a founding member of the Mass General Brigham health care system.
Journal
Cancer Discovery
Method of Research
Randomized controlled/clinical trial
Subject of Research
People
Article Title
Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer
Article Publication Date
23-Mar-2022
COI Statement
The following authors have filed patents related to targeting repeat RNAs and their use as novel biomarkers (MR, AS, KSA, MNR, VD, BDG, DTT). DTT and BDG are co-founders, own equity, and receive consulting fees from ROME Therapeutics, a company developing drugs targeting repetitive RNA expressed in cancers and other diseases. This work was not supported by ROME Therapeutics. DTT’s interests were reviewed and are managed by Mass General Brigham in accordance with their conflict of interest policies. Parts of this work was supported by ACD-Biotechne (ASK, VD, MNR, DTT). DTT has received consulting fees from Tekla Capital Management, Ikena Oncology, NanoString Technologies, Pfizer, Merrimack Pharmaceuticals, Ventana Roche, Foundation Medicine, Inc., and EMD Millipore Sigma, which are not related to this work. DTT is a founder and has equity in PanTher Therapeutics and TellBio, Inc., which are not related to this work. BDG is a consultant or received honoraria for Darwin Health, Merck, PMV Pharma, ROME Therapeutics, Merck, Bristol–Meyers Squibb, and Chugai Pharmaceuticals and has research funding from Bristol-Meyers Squibb. ARP is a consultant/advisory board member for Eli Lilly, Natera, Checkmate Pharmaceuticals, Inivata, and Pfizer; holds equity in C2I; serves on the DSMC for Roche; and has research funding from Puretech, PMV Pharmaceuticals, Plexxikon, Takeda, BMS, Novartis, Genentech, Guardant, Array, and Eli Lilly. MST is a consultant for ROME therapeutics. JWC is author for McGraw Hill and UpToDate. LG is a consultant/advisory board member for Alentis, AstraZeneca, Exelixis, and Sirtex, Genentech, Genentech, H3Biomedicine, Incyte, QED Therapeutics, Servier, and Taiho; and has research funding from Adaptimmune, Bayer, Bristol-Myers Squibb, Eisai, Leap Therapeutics, Loxo Oncology, MacroGenics, Merck, Novartis, Nucana, Relay Therapeutics, Genentech, H3Biomedicine, Incyte, QED Therapeutics, Servier, and Taiho. DPR is a consultant/advisory board member for MPM Capital, Gritstone Oncology, Oncorus, Maverick Therapeutics, 28/7 Therapeutics, Thrive/Exact Sciences; has equity in MPM Capital, Acworth Pharmaceuticals, and Thrive/Exact Sciences; is a legal consultant for Boeringer Ingelheim; and serves as author for Johns Hopkins University Press, UpToDate, McGraw Hill. RBC is a consultant/advisory board member for Abbvie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Elicio, Erasca, Fog Pharma, Genentech, Guardant Health, Ipsen, Kinnate Biopharma, LOXO, Merrimack, Mirati Therapeutics, Natera, Navire, N-of-one/Qiagen, Novartis, nRichDx, Remix Therapeutics, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Tango Therapeutics, Taiho, Warp Drive Bio, Zikani Therapeutics; holds equity in Avidity Biosciences, C4 Therapeutics, Erasca, Kinnate Biopharma, nRichDx, Remix Therapeutics, and Revolution Medicines; and has research funding from Asana, AstraZeneca, Lilly, Novartis, and Sanofi. DRW is an inventor of the Simoa technology and a founder, board member, and equity holder of Quanterix Corporation. Interests of DRW have been reviewed and are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their policies on competing interests. KHB has consulted for Rome Therapeutics, Tessera Therapeutics, Transposon Therapeutics, and is the Scientific Co-founder of Oncolinea Pharmaceuticals. All other authors declare no competing interests.