New SCIENCE publication and recently presented posters detail the IO mechanism-of-action and anti-tumor activity of Dracen’s glutamine antagonist platform

ABOUT US

Dracen is a private pharmaceutical company leveraging immuno-metabolism to create a potential new treatment paradigm with broad application for many cancer types. Our goal in treating cancers is to directly shrink tumors and remodel the tumor microenvironment to make it more conducive to immuno-oncology approaches, to gain greater disease control, increase anti-tumor responses and extend patient survival in areas of unmet need. This includes cancers that possess genetic mutations which may make them highly susceptible to our therapies and those able to evade available immuno-oncology and other standard-of-care approaches.

Our lead candidate, DRP-104, is unique among glutamine inhibitor approaches as it irreversibly inhibits all known enzymes involved in glutamine metabolism resulting in:  
 

  • Single agent anti-tumor activity across a wide spectrum of pre-clinical models
  • Impactful remodeling of the tumor microenvironment, stimulating anti-tumor immune responses
  • Promising curative synergies with checkpoint inhibitors to deliver substantial survival improvement in animal studies, even in models with demonstrated resistance to anti-PD-1 treatment 
Leadership Team
Board of Directors
Scientific Advisory Board
Investors

OUR SCIENCE

Many cancer types are characterized as “glutamine-addicted” and targeting glutamine metabolism offers the potential for stopping tumor growth.  

Operating at the intersection of cancer metabolism and immuno-oncology, our novel series of glutamine antagonists target anti-tumor growth and progression by:

  • Delivering powerful, direct anti-tumor apoptotic properties
  • Remodeling the tumor microenvironment leading to enhanced immune cell function
  • Stimulating anti-tumor immune modulatory mechanisms in T effector, natural killer (NK) and NKT cells, stimulating pro-inflammatory macrophages and inhibiting immune suppressive myeloid-derived suppressor cells 
Our Goal

Tumor-Directed, Broad Acting Glutamine Antagonist

This program was designed to preferentially deliver the active moiety to tumors:

  • DON (6-Diazo-5-oxo-L-norleucine) is the broad acting glutamine antagonist moiety of DRP-104, irreversibly inhibiting all known enzymes involved in glutamine metabolism. 
  • Because glutamine pathway inhibition via DON impacts multiple pathways critical for tumor growth and survival, it has the potential to lead to a broader anti-tumor response. In addition, broad glutamine pathway inhibition has been directly linked to modulating several metabolites leading to immune modulation in the tumor microenvironment. 
  • Broader inhibition of glutamine pathways may reduce the risk for bypass mechanisms and resistance development, potentially leading to more durable responses. 
  • DON was originally developed long before there was a thorough understanding of tumor biology, cancer metabolism and immuno-oncology. Even though it demonstrated robust anti-cancer efficacy in preclinical animal models and showed early signs of clinical benefit in exploratory cancer clinical studies, its therapeutic potential and further development was hampered by dose limiting GI toxicity.

DRP-104, our lead candidate, demonstrates significant advantages over the active moiety “DON”:

  • Potent single agent anti-tumor activity across multiple tumor models with regressions and cures at tolerated doses
  • Combination with checkpoint inhibitors is curative and elicits long-term immune memory response in the CT26 colon cancer cell line
  • Synergy and long-term durable complete responses with anti-PD-L1 in the H22 HCC cancer model
  • Excellent plasma and GI tissue stability  
  • Highly increased tumor biodistribution and targeting 
  • Significantly improved therapeutic window  

Glutamine is the most abundant amino acid in plasma and plays a critical role in cancer metabolism, feeding into the tricarboxylic acid cycle and being used for energy generation as well as providing building blocks for nucleotide, amino acid and lipid biosynthesis to support rapid proliferation. Multiple enzymes are involved in glutamine metabolism and as such, targeting one specific enzyme such as glutaminase may have a limited therapeutic impact. Broadly inhibiting other multiple glutamine-related pathways may potentially be more effective in shutting down tumor growth.

Glutamine is a nutrient used by cancer cells to increase proliferation and survival. In these rapidly dividing cells, glutamine is voraciously consumed as a source of energy, serves as nitrogen and carbon for biomass and is important in cell signaling. Numerous published reports have shown and highlight the breadth of glutamine-addicted tumors.

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PIPELINE

Publications

Papers
Posters

SITC 2019

DRP-104, a novel broad acting glutamine antagonist, induces distinctive immune modulation mechanisms and synergistic efficacy in combination with immune checkpoint blockade
Yumi Yokoyama, Michael Nedelcovych and Robert Wild
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DRP-104, a novel broad acting glutamine antagonist, induces durable anti-tumor responses in vivo by inhibiting tumor glutamine addiction, remodeling the tumor microenvironment and stimulating both the innate and adaptive immune system
Yumi Yokoyama, Michael Nedelcovych and Robert Wild
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AACR 2019

Tumor targeted delivery of glutamine antagonist: Use of CES1-/- Mice
Rana Rais, Jesse Alt, Ranjeet P. Dash, Alexandra J. Gadiano, Lukáš Tenora, Kateřina Novotná, Pavel Majer, Barbara S. Slusher
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Targeting glutamine metabolism disables warburg physiology by inhibiting proximal glycolysis and krebs cycle rewiring
Liang Zhao, Matthew Arwood, Wei Xu, Im-Hong Sun, Im-Meng Sun, MinHee Oh, Chirag Patel, Ryan Jou, Robert Leone, Jesse Alt, Rana Rais, Barbara Slusher, Jonathan D. Powell
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Targeting glutamine metabolism leads to terminal differentiation in acute myeloid leukemia (AML)
Robert D. Leone, Im-Meng Sun, Min-Hee Oh, Roshan Chikarmane, Radhika Viswanathan, Sanjeda Patwari, Matthew Arwood, Gabriel Ghiaur, Jonathan Powell
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Targeting glutamine metabolism as a mean of treating a murine model of ovarian cancer and ascites development
Min‐Hee Oh, Meghan Travers, Stephen Brown, Liang Zhao, Im‐Meng Sun, Im‐Hong Sun, Matthew Arwood, Wei Xu, Samuel Collins, Robert Leone, Eva Prchalova, Rana Rais, Barbara Slusher, Maureen Horton, Cynthia Zahnow, Jonathan Powell
Download

JHU395, a nervous tissue penetrant glutamine antagonist, restricts growth of malignant peripheral nerve sheath tumor with inhibition of nucleotide synthesis
Kathryn M. Lemberg, Liang Zhao, Ying Wu, Vijayabhaskar Veeravalli, Jesse Alt, Joanna Marie H. Aguilar, Lukáš Tenora, Michael Nedelcovych, Cory Brayton, Pavel Majer, Jaishri Blakeley, Rana Rais, and Barbara S. Slusher
Download

 

AACR 2018

Targeting glutamine metabolism as a means of enhancing antitumor T-cell responses
Robert Leone, Judson Englert, Im-Meng Sun, Min-Hee Oh, Jesse Alt, Im-Hong Sun, Ada J. Tam, Pavel Majer, Rana Rais, Barbara Slusher and Jonathan Powell

Glutamine metabolic inhibition synergizes with L-asparaginase in MYCN-amplified neuroblastoma
Micah J. Maxwell, Brad Poore, Allison Hanaford, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart and Eric H. Raabe
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Targeting glutamine metabolism enhances tumor specific immunity by inhibiting the generation and function of suppressive myeloid cells
Min-Hee Oh, Im-Hong Sun, Liang Zhao, Im-Meng Sun, Wei Xu, Chirag Patel, Robert Leone, Ada J. Tam, Judd Englert, Pavel Majer, Rana Rais, Barbara Slusher, Maureen R. Horton and Jonathan D. Powell
Download

Novel prodrugs of the glutamine antagonist 6-diazo-5-oxo-norleucine (DON) as treatment for malignant peripheral nerve sheath tumor
Kathryn Lemberg, Ying Wu, Jesse Alt, Liang Zhao, Alexandra J. Gadiano, Chabely Rodriguez, Rana Rais, Pavel Majer, Jaishri Blakeley and Barbara Slusher
Download

 

AACR 2017

Metabolism as checkpoint: Induction of anti-tumor immune response with the novel glutamine antagonist JHU-083
Robert D. Leone, Judson M. Englert, Min-Hee Oh, Chih-Hsien Cheng, Rana Rais, Barbara Slusher, Jonathan D. Powell
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