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Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, Patel MR, Shapiro GI, Mier JW, Tolcher AW, Wang-Gillam A, Sznol M, Flaherty K, Buchbinder E, Carvajal RD, Varghese AM, Lacouture ME, Ribas A, Patel SP, DeCrescenzo GA, Emery CM, Groover AL, Saha S, Varterasian M, Welsch DJ, Hyman DM, Li BT.Cancer Discovery. Published online Dec 15, 2017, DOI: 10.1158/2159-8290.CD-17-1119.

Seaman S, Zhu Z, Saha S, Zhang XM, Yang MY, Hilton MB, Morris K, Szot C, Morris H, Swing DA, Tessarollo L, Smith SW, Degrado S, Borkin D, Jain N, Scheiermann J, Feng Y, Wang Y, Li J, Welsch D, DeCrescenzo G, Chaudhary A, Zudaire E, Klarmann KD, Keller JR, Dimitrov DS, St Croix B. Cancer Cell. 2017;31:501-515.e8.

Zhang XM, Zhang HH, McLeroth P, Berkowitz RD, Mont MA, Stabin MG, Siegel BA, Alavi A, Barnett TM, Gelb J, Petit C, Spaltro J, Cho SY, Pomper MG, Conklin JJ, Bettegowda C, Saha S. Nuclear Med Biol. 2016;43:273-279.

Zheng L, Zhang Z, Khazaie K, Saha S, Lewandowski RJ, Zhang G, Larson AC. PloS One. 2014;9:e116204.

Roberts NJ, Zhang L, Janku F, Collins A, Bai RY, Staedtke V, Rusk AW, Tung D, Miller M, Roix J, Khanna KV, Murthy R, Benjamin RS, Helgason T, Szvalb AD, Bird JE, Roy-Chowdhuri S, Zhang HH, Qiao Y, Karim B, McDaniel J, Elpiner A, Sahora A, Lachowicz J, Phillips B, Turner A, Klein MK, Post G, Diaz LA, Jr., Riggins GJ, Papadopoulos N, Kinzler KW, Vogelstein B, Bettegowda C, Huso DL, Varterasian M, Saha S, Zhou S. Sci Transl Med. 2014;6:249ra111.

Roix JJ, Harrison SD, Rainbolt EA, Meshaw KR, McMurry AS, Cheung P, Saha S. PloS One. 2014;9:e101708.

Tung D, DeCrescenzo G, Welsch D, Cheung PH, Bettegowda C, Saha S. World J Microbiol Biotechnol. 2014;30:3003-3010.

Roix J, Saha S. BMC Nephrol. 2013;14:233.

Tung D, Ciallella J, Hain H, Cheung PH, Saha S. Curr Ther Res Clin Exp. 2013;75:71-76.

Tung D, Ciallella J, Cheung PH, Saha S. Pharmacology. 2013;91:29-34.

Tung D, Cheung PH, Wilson J, Tudor G, Booth C, Saha S. Curr Ther Res Clin Exp. 2012;73:150-164.

Roix JJ, DeCrescenzo GA, Cheung PH, Ciallella JR, Sulpice T, Saha S, Halse R. Diabetes Obes Metab. 2012;14:329-334.

Tung D, Cheung PH, Ciallella J, Saha S. Pharmacology. 2011;88:295-301.

Tung D, Cheung PH, Tudor G, Booth C, Saha S. Curr Ther Res Clin Exp. 2011;72:262-272.

Tung D, Cheung PH, Kaur P, Foreman O, Kavirayani A, Hain HS, Saha S. Pharmacology. 2011;88:100-113.

BioMed Valley Discoveries and collaborators published an article online December 15, 2017, in Cancer Discovery summarizing clinical trial results of first-in-class ERK-targeted cancer therapy ulixertinib (BVD-523). A press release was issued by the American Association for Cancer Research (AACR).

Press Release

Kansas City, MO. — A preclinical study indicates that ulixertinib (BVD-523) holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting the MAPK pathway. A third of all human cancers are driven by mutations in this pathway.

The study, sponsored by BioMed Valley Discoveries, was published online in Molecular Cancer Therapeutics.Supported by these preclinical findings, clinical trials of ulixertinib were initiated. A Phase 1/2a clinical trial was recently completed and additional trials are currently underway.

“Our findings suggest that targeting ERK activity, the most downstream kinases of the MAPK signaling pathway, may be a rational cornerstone therapy for many tumors,” said Dean Welsch, Ph.D., Head of Pharmacology at BioMed Valley Discoveries and lead study author. “ERK inhibitors may have the potential to address issues of drug resistance that have plagued other targeted therapies.”

The mitogen-activated protein kinase (MAPK) signaling pathway is one of the most well studied pathways in human biology. This pathway behaves like an intracellular series of switches. A signal activates a cell receptor, which in turn activates RAS, which activates RAF, which activates MEK, which then activates ERK. Switched-on ERK activates numerous targets that enable a cell to grow, proliferate, and survive. In this way, ERK plays a key role in communicating extracellular signals that drive key cellular functions. In many types of cancer, this highly coordinated series of cascading events becomes dysregulated, often as a result of mutations. Dysregulation of the pathway causes cells to grow out of control. Because of its established importance in numerous cancers, this pathway has been the focus of drug discovery efforts for many years.

While no compounds have effectively targeted RAS, drugs designed to inhibit RAF or MEK have improved clinical outcomes for patients with metastatic melanoma and other tumor types. Unfortunately, the majority of patients given these targeted therapies eventually develop resistance to the drugs, and their disease progresses. Because ERK resides at the end of the MAPK signaling pathway, ERK inhibition may provide a unique opportunity to extend the duration of response seen with available treatments.

Results in this study characterizing ulixertinib included the demonstration of potential anti-tumor activity in preclinical in vitro assays as well as in vivo models, including studies designed to exemplify the potential for treating patients who had never received a pathway inhibitor and those that had acquired resistance. The authors showed that ulixertinib could arrest the growth of cancer cell lines in the laboratory. Furthermore, they demonstrated that the drug could inhibit the growth of tumors, and even cause them to regress in BRAFand RAS mutant xenograft models. Studies investigating ulixertinib in combination with BRAF inhibitors highlighted the potential for using this agent with existing therapies.

Importantly, cells engineered to be resistant to current therapies were found to retain their sensitivity to ulixertinib. This finding with single-agent ulixertinib was confirmed and extended using in vivo resistance models.

Finally, the researchers studied the emergence of resistance to ulixertinib. They found that single-agent treatment of cancer cells with ulixertinib was quite durable and that it was more challenging to develop resistance to ulixertinib than other agents targeting upstream components of the MAPK signaling pathway.

“Because the ERK inhibitor targets the last step in this pathway, we think ulixertinib has the potential to effectively address aberrant pathway signaling resultant from upstream dyregulation – including those as a consequence of mutations to RAS, RAF, MEK, or ERK,” said Welsch. “These encouraging preclinical studies suggest multiple opportunities for ulixertinib in various cancers. We look forward to the results from ongoing/planned clinical trials to help define how this agent might eventually help cancer patients”.

BioMed Valley Discoveries launched and successfully completed a multi-center clinical trial of the drug in patients with metastatic or advanced-stage cancer. The company also has several investigator-initiated trials planned or underway looking at other indications for ulixertinib, alone and in novel combination therapy regimens.

Ulixertinib received US Food and Drug Administration (FDA) Fast Track designation in September 2015, which allows for an expedited FDA review of drugs and therapies that treat a serious or life-threatening condition and fill an unmet medical need. Vertex Pharmaceuticals Inc discovered ulixertinib. BioMed Valley Discoveries licensed the compound at the clinical candidate stage and has advanced the compound from the late preclinical stage to the completion of Phase 1/2a.

Co-authors of the study include Ursula A. Germann, Brinley F. Furey, William Markland, Russell R. Hoover, Alex M. Aronov, Michael Hale, Diane M. Boucher, Gabriel Martinez-Botella, Matthew Fitzgibbon, and Mark Namchuk of Vertex Pharmaceuticals Inc; Jeffrey J. Roix, Anna Groover, Gary DeCrescenzo, Caroline M. Emery, and Saurabh Saha of BioMed Valley Discoveries; David A. Sorrell of Horizon Discovery Ltd; Paul Shapiro and Ramin Samadani of University of Maryland School of Pharmacy; Michael J. Wick of START; and Kathryn Meshaw of Charles River Discovery Services. The study was funded by BioMed Valley Discoveries.

About BioMed Valley Discoveries (BVD)

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Kansas City, MO. — Deep within most tumors lie areas that remain untouched by chemotherapy and radiation. These troublesome spots lack the blood and oxygen needed for traditional therapies to work, but provide the perfect target for a new cancer treatment using bacteria that thrive in oxygen-poor conditions. Now, researchers have shown that injections of a weakened version of one such anaerobic bacteria — the microbe C lostridium novyi — can shrink tumors in rats, pet dogs, and a human patient.

The findings from BioMed Valley Discoveries and a nationwide team of collaborators demonstrate that C. novyi-NT, a version without the ability to make certain toxins, can act as a new type of “biosurgery” to eat away tumors in hard to reach places. The bacteria excise tumor tissue in a precise, localized way that spares surrounding normal tissue. The study — which represents a new take on an approach first attempted a century ago — indicates that further testing of this agent in selected patients is warranted.

“We have encouraging signs that this bacteria could be used to treat certain inoperable tumors, and that could give hope to some patients who don’t have any other options,” said Saurabh Saha, M.D., Ph.D., a longtime cancer researcher at BioMed Valley Discoveries and senior author of the study. “But we are still in the early stages, and need to further assess the safety and efficacy of the treatment, as well as explore how well it works in combination with other cancer therapies.”

The study was published August 13, 2014, in Science Translational Medicine.

The idea of using bacteria to combat cancer dates back to the 1890’s, when cancer researcher William Coley noticed that some patients who developed postsurgical infections went into remission or were even cured of their disease. Despite the approach’s initial promise, progress was slow for the next century.

Over a decade ago Bert Vogelstein, M.D., a cancer researcher at the Johns Hopkins School of Medicine and one of the study co-authors, tested a number of microbes before identifying a particularly promising one called Clostridium novyi. Because C. novyi is exquisitely sensitive to oxygen, it would grow inside the oxygen-poor core of tumors but stop once it reached healthy tissue. In previous studies, Vogelstein and his colleagues tamed the bacteria further by removing its ability to make toxins and then injected it intravenously into laboratory animals. Though the bacterial treatment had dramatic effects in a third of the mice and rabbits, no complete responses were seen in dogs with naturally occurring cancers.

Dr. Saha and his colleagues at BioMed Valley Discoveries wondered if this failure was due more to the route of administration than to the therapy itself. One issue with intravenous delivery is the small proportion of spores that actually make it to the tumors. The researchers hypothesized that injecting the spores directly into tumors would not only overcome this problem, but might also trigger localized inflammatory and immune responses against tumor cells.

The researchers tested C. novyi-NT via directly injecting the bacteria into tumors in pet dogs with naturally occurring cancers and whose owners volunteered them for the trial. Each dog received between one and four cycles of the new treatment, consisting of a single injection of 100 million spores directly into the target tumor. Of sixteen dogs evaluated after treatment, three had significant shrinkage of their tumors and three had tumors that were completely destroyed.

The next step was to attempt the treatment in humans. The first patient to enroll in this Phase I investigational study was a 53-year old woman with retroperitoneal leiomyosarcoma whose disease, despite eight rounds of chemotherapy and radiation, had spread to her liver, lungs, abdomen, upper arm, and shoulder. The researchers injected 10,000 spores into the patient’s metastatic right shoulder tumor. Within days, CT scans and biopsies demonstrated that the bacteria had infiltrated the tumor and had begun destroying tumor cells. Weeks later, a follow-up MRI showed that a significant amount of tumor had been destroyed. As a result of treatment, the patient’s shoulder pain subsided and she was able to move her arm again.

Studies in other patients are currently underway at multiple sites to test the safety and efficacy of this new approach. Though these results are preliminary, the researchers believe that C. novyi-NT could potentially become part of a new arsenal of immunotherapies that prime a patient’s immune system to fight off cancer.

“Earlier pre-clinical studies showed that in the process of destroying cancer tissue, C. novyi-NT generates a potent innate immune response which also contributes to the localized tumor destruction,” said Dr. Saha. “The hope is that C. novyi-NT will be a useful adjuvant to the new immune checkpoint inhibitors that can block the ability of tumors to evade a host mediated immune response. It will be interesting to see if a combination of the two approaches could destroy tumors not just at the injection site, but also at any other sites where the cancer may have spread to throughout the body.”

Study co-authors from BioMed Valley Discoveries are: Linping Zhang, Amanda Collins, David Tung, Maria Miller, Jeffrey Roix, Halle H. Zhang, and Mary Varterasian. Other co-authors include Nicholas J. Roberts, Yuan Qiao, Luis A. Diaz Jr., Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Chetan Bettegowda, and Shibin Zhou of the Johns Hopkins Kimmel Cancer Center’s Ludwig Center; Filip Janku, Thorunn Helgason, Ravi Murthy, Robert S. Benjamin, Ariel D. Szvalb, Justin E. Bird, and Sinchita Roy-Chowdhuri of The University of Texas MD Anderson Cancer Center; Ren-Yuan Bai, Verena Staedtke, and Gregory J. Riggins of the Johns Hopkins Medical Institutes Department of Neurosurgery; Anthony W. Rusk and Kristen V. Khanna of Animal Clinical Investigation, LLC; Baktiar Karim and David L. Huso of the Johns Hopkins University Department of Molecular and Comparative Pathobiology; Jennifer McDaniel and Gerald Post of The Veterinary Cancer Center; Amanda Elpiner of VCA Great Lakes Veterinary Specialists; Alexandra Sahora of The Oncology Service, Friendship Hospital for Animals; Joshua Lachowicz of BluePearl Veterinary Partners; Brenda Phillips of Veterinary Specialty Hospital of San Diego; Avenelle Turner of Veterinary Cancer Group of Los Angeles at City of Angels Veterinary Specialty Center; and Mary K. Klein of Southern Arizona Veterinary Specialty and Emergency Center.

The study was funded by BioMed Valley Discoveries, Inc., the Virginia and D.K. Ludwig

Fund for Cancer Research, the Maryland Cigarette Restitution Fund, the Commonwealth Fund, Swim Across America, the Burroughs Wellcome Career Award for Medical Scientists, Voices Against Brain Cancer, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins Clinician Scientist Award, and National Institutes of Health (National Cancer Institute award numbers CA129825 and CA062924, and National Institute of Neurological Disorders and Stroke award number R25NS065729) funded the research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

About BioMed Valley Discoveries

BioMed Valley Discoveries, Inc. is a for-profit, disease-related research and development organization, whose mission is to address unmet medical needs in areas that are considered too early, too unconventional or too unprofitable for traditional biotech and pharmaceutical companies. Operating since 2007, BVD advances its mission with commercial capabilities and resources typically unavailable to academic institutions. As a member of the Stowers Group of Companies, BVD receives its funding principally from an endowment supporting the Stowers Institute for Medical Research, a non-profit 550-person basic biomedical research organization. One hundred percent of the profits from BVD will also accrue to the benefit of the Stowers Institute. James Stowers, Jr., founder of American Century Investments, and his wife Virginia established BioMed Valley Discoveries and the Stowers Institute for Medical Research. Together, Jim and Virginia Stowers have endowed the Institute with over $2 billion in donations, including a controlling interest in American Century Investments. Since it began operations in 2000, the Institute has received and spent over $1 billion in dividends from its ownership stake in American Century Investments.

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