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.”


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.

Adapted from press release by European Society of Medical Oncology.

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.