New targeted epigenetic therapy for lymphoma shows promise

New compounds targeting epigenetics have shown promise in treating patients with lymphoma, according to data presented at the Targeted Anticancer Therapies International Congress 2018 in Paris, France. ESMO’s phase-I oncology meeting featured early clinical studies with BET inhibitors and EZH2 inhibitors.

Dr. Anastasios Stathis, head of the New Drugs Development Unit of the Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland, was one of the first oncologists to research this field. He said BET inhibitors had shown some activity in leukemia, lymphoma and also a rare and aggressive solid tumor driven by a translocation involving BET genes called NUT carcinoma. His previous phase I research on the first-in-class BET inhibitor birabresib (OTX015/MK-8628) showed some activity in diffuse large B-cell lymphoma, providing proof-of-concept for this approach. (1)

Subsequently, birabresib was used on a single-patient compassionate basis in four patients with NUT carcinoma. Stathis said: “This was the first evidence that preclinical findings with BET inhibitors in models of NUT carcinoma could be translated into activity in patients.” (2)

Multiple BET inhibitors have been studied in clinical trials, and preliminary results have confirmed that they may be effective in patients with diffuse large B-cell lymphoma and NUT carcinoma. (3) Some of the significant side effects include Thrombocytopaenia which appears to be dose-limiting and is reversible and not accompanied by major bleeding events, fatigue and gastrointestinal symptoms.

Regarding activity, patients do eventually progress on treatment, and the duration of response is unknown. Stathis said: “It’s not clear what the real clinical impact of BET inhibitors could be. Compounds approved for lymphoma in the last five years had single-agent phase-I response rates above 30%, but activity with BET inhibitors is less than 30%. The hope is to identify the patients that would benefit most and test BET inhibitors in combination with other compounds. Also, there are new classes of BET inhibitors in preclinical studies, and we need to wait to see if they have better activity.”

Another area where clinical data is emerging is related to EZH2 inhibitors for which data will be presented at Targeted Anticancer Therapies International Congress 2018. EZH2 is a protein that exhibits relatively frequent mutations in lymphoma. Results will be presented from a study in patients with B-cell lymphoma showing evidence of antitumor activity with an EZH2 inhibitor, which was well tolerated and had manageable toxicities. (4) Study author Dr. Adrian Senderowicz of Constellation Pharmaceuticals, Cambridge, US, said: “If approved by health authorities, EZH2 inhibition may become a new treatment paradigm in relapse or refractory EZH2 mutant follicular lymphoma patients.”

A previous study showed that another EZH2 inhibitor, tazemetostat, induced objective response rates of 92% in patients with EZH2 mutant follicular lymphoma and 26% in those with the wild-type. (5) Stathis said: “The question is whether it makes sense to treat patients without the mutation since the response is so much lower. However, these patients do show some response and researchers want to know why.”

Stathis said: “We do have proof, and we will see further evidence at TAT 2018, that epigenetics are a promising target in lymphomas.”

Citations:

1 Amorim S, Stathis A, Gleeson M, et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016;3(4):e196-204. doi: 10.1016/S2352-3026(16)00021-1.

2 Stathis A, Zucca E, Bekradda M, et al. Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628. Cancer Discov. 2016;6(5):492-500. doi: 10.1158/2159-8290.CD-15-1335.

3 Stathis A, Bertoni F. BET Proteins as Targets for Anticancer Treatment. Cancer Discov. 2018;8(1):24-36. doi: 10.1158/2159-8290.CD-17-0605.

4 Abstract 42O ‘A Phase 1 Study of CPI-1205, a Small Molecule Inhibitor of EZH2, Preliminary Safety in Patients with B-Cell Lymphomas’: presented by Adrian Senderowicz during Proffered Paper Session 2 on Tuesday, 6 March, 11:00 to 12:30 (CET) in Room Scene AB.

5 Morschhauser F, Salles G, McKay P, et al. Interim report from a phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory B-cell non-Hodgkin lymphomas. Hematol Oncol. 2017;35(S2):24-25. https://doi.org/10.1002/hon.2437_3

Adapted from press release by European Society of Medical Oncology.

Novel and unique DNA vaccine to fight effectively against cancer antigen

Scientists at The Wistar Institute and Inovio pharmaceuticals, Inc. have devised a unique deoxyribonucleic acid (DNA) vaccine approach through molecular design to boost the immune responses induced against one of the most important cancer antigen targets. Research results were published in the journal Molecular Therapy.

Cancer immunotherapy approaches, designed to harness the body’s natural immune defenses to focus on and kill cancer cells, are showing great promise for cancer treatment and prevention. DNA vaccines can induce immunity through the delivery by an intramuscular injection of a sequence of synthetically designed DNA that contains the instructions for the immune cells in the body to become activated and target a particular antigen against which an immunologic response is wanted.

Despite being specific for cancer cells, cancer tumor-associated antigens generally trigger weak immune responses as a result of they’re recognized as self-antigens and also the body has in place natural mechanisms of immune acceptance, or “Tolerance”, that forestall autoimmunity and also additionally limit the efficacy of cancer vaccines. This is often the case of Wilm’s tumor gene 1 (WT1), a cancer tumor antigen that’s overexpressed in many varieties of cancer and possibly plays a key role in driving tumor development. vaccine approaches against WT1 thus far haven’t appeared promising because of immune tolerance leading to poor immune responses against cancers expressing WT1.

Wistar scientists have developed a unique WT1 deoxyribonucleic acid (DNA) vaccine employing a strategically changed DNA sequence that tags the WT1 as foreign to the host immune system breaking tolerance in animal models.

“This is an important time in the development of anti-DNA cancer immune therapy approaches. This team has developed an approach that may play an important role in generating improved immunity to WT1 expressing cancers,”said David B. Weiner, Ph.D., Executive Vice President and Director of the Vaccine Center at The Wistar Institute and the W.W. Smith Charitable Trust Professor in Cancer Research, and senior author of the study.”These immune responses represent a unique tool for potentially treating patients with multiple forms of cancer. Our vaccine also provides an opportunity to combine this approach with another immune therapy approach, checkpoint inhibitors, to maximize possible immune therapy impact on specific cancers.”

The team lead by Weiner has optimized the dna vaccine employing a artificial dna sequence for WT1 that, while maintaining a very high similarity with the native sequence, contains new modified sequences that differ from native WT1 in an attempt to render it more recognizable by the host immune system. The novel WT1 vaccine was superior to a more traditional native WT1 vaccine because it was able to break immune tolerance and induce long-term immune memory. Significantly, the vaccine also stimulated a therapeutic anti-tumor response against leukemia in mice.

Citation: Walters, Jewell N., Bernadette Ferraro, Elizabeth K. Duperret, Kimberly A. Kraynyak, Jaemi Chu, Ashley Saint-Fleur, Jian Yan, Hy Levitsky, Amir S. Khan, Niranjan Y. Sardesai, and David B. Weiner. “A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity.” Molecular Therapy, 2017. doi:10.1016/j.ymthe.2017.01.022.
Research funding: Inovio Pharmaceuticals, Inc. Basser Center for BRCA/Abramson Cancer CenterWeiner, W.W. Smith Charitable Trust Professorship for Cancer Research.
Adapted from press release by The Wistar Institute.

Piperlongumine, chemical from Indian pepper plant inhibits enzyme in cancer cells

UT Southwestern Medical Center scientists have uncovered the chemical process behind anti-cancer properties of a spicy Indian pepper plant called the long pepper, whose suspected medicinal properties date back thousands of years. The study is published in the Journal of Biological Chemistry.

Dr. Westover’s lab used X-ray crystallography to create this molecular model of piperlongumine.
Credit: UT Southwestern

The secret lies in a chemical called Piperlongumine (PL), which has shown activity against many cancers including prostate, breast, lung, colon, lymphoma, leukemia, primary brain tumors, and gastric cancer.

Using x-ray crystallography, researchers were able to create molecular structures that show how the chemical is transformed after being ingested. Piperlongumine (PL) converts to hPiperlongumine (hPL), an active drug that silences a gene called GSTP1. The GSTP1 gene produces a detoxification enzyme Glutathione S-Transferase Pi 1 that is often overly abundant in tumors.

“We are hopeful that our structure will enable additional drug development efforts to improve the potency of PL for use in a wide range of cancer therapies,” said Dr. Kenneth Westover, Assistant Professor of Biochemistry and Radiation Oncology. “This research is a spectacular demonstration of the power of x-ray crystallography.”

Dr. Westover, a member of the Harold C. Simmons Comprehensive Cancer Center, used cutting edge technologies in UT Southwestern’s Structural Biology Core (SBC) – the University’s world-renowned facility for X-ray crystallography, to better understand the anticancer properties of Piperlongumine (PL). X-ray crystallography allows scientists to determine molecular structures that reveal how molecules interact with targets – in this case how Piperlongumine (PL) interacts with GSTP1. Viewing the structures helps in developing drugs for those targets.

Citation: Harshbarger, Wayne, Sudershan Gondi, Scott B. Ficarro, John Hunter, Durga Udayakumar, Deepak Gurbani, William Singer, Yan Liu, Lianbo Li, Jarrod A. Marto and Kenneth D. Westover. “Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine.” Journal of Biological Chemistry (2016): jbc-M116.
DOI: 10.1074/jbc.M116.750299
Research funding: V Foundation for Cancer Research, Welch Foundation, and Cancer Prevention and Research Institute of Texas.
Adapted from press release by UT Southwestern Medical Center.

Understanding Leukemia cell movement gives clues to its resistance to treatment

This is a high-resolution render of unique environments in the bone marrow (blue,
purple and green) as they are invaded and populated by leukemia cells (yellow).
Credit: Edwin Hawkins and Delfim Duarte/Imperial College London

New research is shedding light on how leukaemia cells can survive cancer treatment, suggesting new possibilities for stopping them in their tracks. Leukaemia has one of the highest cancer mortality rates. This is partly because there is a high relapse rate, as some cancer cells can survive the initial treatment. These surviving cells are often resistant to treatment, allowing the cancer to spread and become fatal. These findings were published in Nature.

How these treatment-resistant cells survive initial chemotherapy is not well understood. One popular theory has been that they sit hiding in specific niches within the bone marrow that usually harbour blood stem cells – basic cells that can become all other blood cells.

However, new research in mice, and validated with human samples, has revealed that certain leukaemia cells do not sit and hide. The research was led by a team at Imperial College London with colleagues from the Francis Crick Institute in London and the University of Melbourne in Australia, and is published today in Nature. Instead, to the researchers’ surprise, the cells were scattered throughout the mouse bone marrow both before and after treatment, and they were moving around rapidly.

After treatment, the leukaemia cells that survived were seen moving faster than those before treatment. The researchers suggest that the act of moving itself may help the cells to survive, possibly through short-lived interactions with an array of our own cells.

The team’s investigation into leukaemia cells’ behaviour also revealed that they actively attack bone cells, which are known to support healthy blood production. The researchers believe this insight could help scientists to develop treatments to safeguard production of healthy blood cells in leukaemia patients.

To investigate the working of leukaemia at the cellular level, the team used a technique called intravital microscopy that allows high-resolution fast imaging of live animals. The team used mice with a particularly deadly type of leukaemia called T cell acute leukaemia and tracked the movement of disease cells before and after treatment.

The research was funded by the charities Bloodwise and Cancer Research UK, alongside contributions to buy equipment and recruit team members from the European Research Council, the Human Frontier Science Program, and the European Hematology Association.

Publication: T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments.
DOI: http://dx.doi.org/10.1038/nature19801
Authors: Edwin D. Hawkins et.al.,
Research funding: Bloodwise, Cancer Research UK, European Research Council, Human Frontier Science Program, and European Hematology Association.
Adapted from press release by Imperial College London