Research Overview:
Dr. Gudkov’s laboratory is conducting a broad research program involving several distinct but highly integrated branches of study. These include studying stress response pathways, such as p53 and NF-kB, intrinsic mechanisms of DNA damage and control of genomic stability, and the role of inflammation in cancer development and progression. Stress associated with cancer treatment is a major direction of his research that involves developing therapies aimed at reducing side effects of radiation and chemotherapy and improving the quality of life of cancer survivors. This line of research is closely connected with studying mechanisms that control longevity and aging, the major current focus of the lab. A series of novel anticancer and antiaging agents have been developed in collaboration with biotech companies that were spun off Gudkov’s lab to focus on the development of these drug candidates that are at different stages of preclinical and clinical development.
Understanding and counteracting cancer treatment side effects
Advances in cancer therapies result in a rapidly growing number of cancer survivors, whose quality post-cancer health has become an increasingly significant medical problem. In fact, even successful cancer treatment is frequently associated with the acquisition of side effects affecting their quality of life and longevity. Dr. Gudkov’s lab pioneered understanding mechanisms behind major cancer treatment side effects and developing approaches to prevent and treat them. Tumor suppressor p53 was identified as a mediator of excessive suicidal cell death following radiation and chemotherapy, and suppression of p53 pro-apoptotic function as a method of preventing such side effects. His works published in Nature, Science and other top-level journals opened a new area in the p53 field: pathologies associated with p53 activity.
To counteract p53-driven damage to healthy tissues during cancer treatment, Dr. Gudkov’s team developed several p53 inhibitory agents and demonstrated their efficacy in animal models of diseases mimicking cancer treatment side effects in humans. The most advanced among these classes of agents were developed based on another major mechanistic discovery: the ability of NF-kappaB inflammation regulatory pathway to suppress p53 function. NF-kappaB activating molecule, an agonist of innate immunity receptor TLR5 named entolimod, has been developed that demonstrated exceptional tissue-protective activities from radiation, chemotherapy and other DNA damaging stresses. Entolimod is a clinical-stage drug candidate developed for multiple indications, including treatment of lethal acute radiation syndrome caused by nuclear disasters. It represents a new class of radiation countermeasures. Entolimod also possesses the activity of anticancer immunotherapeutic. Dr. Gudkov’s laboratory continues studies aimed at developing new generations of TLR5 agonists (e.g., GP532, a deimmunized version of entolimod) and broadening their therapeutic indications via better understanding mechanisms of their activity.
Novel anticancer target and drug discovery
Dr. Gudkov pioneered new approaches to target and drug discovery. He developed several functional genomic methodologies that are based on the use of libraries of gene repressors. These include Genetic Suppressor Element (GSE; developed in collaboration with Igor Roninson) and Selection-Subtraction Approach (SSA) – the techniques, which were successfully applied to identify new genes encoding potential tumor suppressors and other disease-associated genes and deciphering molecular mechanisms of activity of their products as potential targets for therapeutic modulation by small molecules or peptides. The discovery of the cancer association of ING family of genes is one of the hallmarks of the success of this effort.
Gudkov lab was among the first who utilized the power of small molecule library screening for drug discovery. Starting from the discovery of new p53 inhibitors and testing their potential therapeutic applications for reducing cancer treatment side effects and possibly other pathologies involving p53-inducing stresses, he then successfully used chemical libraries to screen for bioactive small molecules for potential anticancer, tissue-protective and antiviral use (e.g., p53 inhibitors pifithrins and, a suppressor of tumor multidrug resistance mechanism reversan, p53 activator in HPV-driven tumors retra, etc.). Several of them, after hit-to-lead optimization, have reached clinical stage and are currently undergoing clinical trials. These include multitargeted non-covalent DNA binder and chromatin modifier curaxin, and inhibitor of nicotinamide phosphoribosyl transferase (NAMPT) OT-82. Curaxin has opened a new class of chromatin-targeting drugs and a new direction in cancer epigenetics being successfully developed by Dr. Katerina Gurova. OT-82 is a novel NAMPT inhibitor that showed exceptional efficacy in preclinical models of hematologic malignancies. Both are currently undergoing multicenter clinical trials.
Another anticancer drug candidate developed in Gudkov lab, Mobilan, stemmed from exploring the immunotherapeutic properties of TLR5 agonists. This recombinant adenovirus for intratumor injections induces simultaneous expression of TLR5 receptor and agonist (modified entolimod) in tumor cells thus enabling antitumor vaccination. It has successfully passed through Phase I clinical trial in prostate cancer patients.
Antiaging research
Most recent direction of Dr. Gudkov’s research is aimed at understanding mechanisms of mammalian aging and developing therapies for prevention and treatment of aging-associated frailty and other pathologies, including cancer. He is following highly original research path that connects aging with gradual accumulation in healthy tissues of pathogenic somatic cells with DNA damaged by the activity of ‘retrobiome’ – a large family of highly repetitive virus-like genetic elements replicating via mechanism of reverse transcription and named retrotransposons or retroelements. Gudkov lab pioneered demonstration of retrobiome silencing control by p53 and activation of interferon as a response to stress associated with its desilencing. This phenomenon, named TRAIN (for Transcription of Repeats Activates Interferon), is a new major tumor suppressor mechanism that highlighted major role of retrobiome activation in cancer and aging. TRAIN concept opened several prophylactic therapeutic opportunities that are based on pharmacological suppression of retrobiome expansion (using small molecule inhibitors of enzymatic activities of reverse transcriptase of LINE-1 retrotransposons) and immunotherapeutic eradication of cells with activated retrobiome. Both these directions are being explored by Gudkov’s lab within an antiaging Quality of Life and Longevity program, that includes, besides drug discovery, also new diagnostic methodologies and development of a solid bioinformatic platform for retrobiome analysis.
Another aspect of Gudkov’s antiaging platform involves reverting of immunosenescence – a general functional decline of immunity observed in elderly. Here he is using a strong immunostimulatory power of TLR5 agonists, initially developed as radiation antidotes, that are now being tested as agents capable of restoration of vaccination capabilities in geriatric population. This hypothesis is being tested in a collaborative clinical trial currently ongoing at Mayo Clinic in collaboration with Drs. Robert Pignolo and James Kirkland.
Biotechnological activities
New disease treatment concepts and bioactive molecules with therapeutic potential discovered in Gudkov’s lab undergo further development into new therapeutics by several biotech startups that were spun out of Dr. Gudkov’s lab. These include Cleveland Biolabs, Inc. (http://www.cbiolabs.com/) (NASDAQ = CBLI) that develops radioprotective indications of entolimod, Incuron, Inc. https://incuron.com/ that runs clinical program of studying anticancer potential of curaxin, Panacela Labs, Inc. (http://www.panacelalabs.com/) that develops immunotherapeutic Mobilan; Oncotartis, Inc. (http://oncotartis.com/) that conducts clinical trial of OT-82 in patients with hematologic malignancies; and Genome Protection, Inc. (GPI) (https://genomeprotection.com/) that runs broad antiaging drug discovery and development R&D program.
Besides biotech startups, Dr. Gudkov founded a non-for-profit biomedical research entity, Vaika, Inc. (https://www.vaika.org/), that conducts clinical research in collaboration with Cornell University School of Veterinary and is aimed at understanding and extending healthspan and lifespan of domestic dogs (research facility located at Cornell University, Ithaca, NY).
All companies continue close basic and clinical research collaboration with Roswell Park based on joint grants and contracts ongoing under Dr. Gudkov’s coordination and supervision.
Academic collaborators:
• Michelle Haber, Ph.D. & Murray Norris, Ph.D. (Children's Cancer Institute of Australia, Sydney)
• Leonid Brodsky, PhD (Tauber Center for Bioinformatics, University of Haifa, Israel)
• Ekaterina Andrianova, PhD, Brandon Hall, PhD, Anatoli Gleiberman, PhD, Lioubov Korotchkina, PhD (Genome Protection, Inc.)
• Robert Pignolo, MD, PhD and James Kirkland, MD, PhD (Mayo Clinic)
• Vera Gorbunova, PhD and Andrei Seluanov, PhD (University of Rochester)
• Peter Fedichev (GERO, Singapore)
• Albert Pinhasov, PhD (Center for Personalized Medicine, Ariel University, Israel)
• Andrei Osterman, PhD (Sanford Burnham Prebys Medical Discovery Institute)
• Olga Chernova, PhD (Oncotartis, Inc.)
• Mikhail Nikiforov, Ph.D. (Wake Forest Comprehensive Cancer Center)
• Natalia Isaeva, PhD (University of North Carolina)
• Denis Logunov, PhD, DSci and Boris Naroditsky, PhD, DSci (Gamaleya Institute of Microbiology, Russia)
• Marianna Yakubovskaya, PhD, DSci (N.N. Blokhin National Cancer Center, Moscow, Russia)
• Marina Antoch, PhD, Sandra Gollnick, Katerina Leonova, PhD, Craig Brackett, PhD, PhD, Joseph Skitzki, MD, Katerina Gurova, MD, PhD, Robert Plunkett, MD, Scott Abrams, PhD, Aimee Stablewski, PhD (Roswell Park Comprehensive Cancer Center)
