Research Interests

Immune Oncology

We are fascinated by the ability of tumors to evade immune elimination. Most of our current programs focus on restoring the power of the immune system to achieve clean tumor kills. Tumors subvert immunity in a variety of ways. They can hide their very existence from innate cellular alarm systems and circulating surveillance immune cells, frustrate the buildup and amplification of immune responses and subvert established inflammatory responses by evoking potent immunosuppressive factors.

The recent approvals of inhibitors targeting checkpoint blockade are the first steps in the establishment of immuno-oncology as durable method of treating a number of cancers. The coming decade will see the emergence of new generations of immune system targeted oncology drugs which can be used as monotherapy or in combination with other immuno-oncology agents or existing drugs.

• The TDO/IDO program focuses on relieving immune suppression caused by products of the kynurenine pathway. Greater than 90% of ingested tryptophan is metabolized by the heme containing oxidoreductase enzymes indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO) to kynurenine which is further metabolized to bioactive intermediates. High levels of tryptophan metabolites create a tolerogenic environment by increasing the number of circulating regulatory T cells and driving CD8+ T cells to apoptosis. Activating the kynurenine pathway in the tumor microenvironment enables tumors to resist checkpoint blockade drugs that target CTLA4 or PD-L1/PD1. Curadev has developed potent small molecule drug candidates that reduce kynurenine levels in biological tissues. These molecules fall into two classes – IDO specific inhibitors and first in class TDO/IDO dual inhibitors which are being developed in partnership with Roche. The therapeutic goal is to combine these molecules with other immune check point inhibitors or specific cytotoxic therapies to potentiate immune response against various types of tumors.
• The STING agonist program focuses on kick-starting an innate immune response in tumors which are devoid of a T cell infiltrate and are consequently immunologically silent. Generating a Type I Interferon response in these non-inflamed tumors leads to the activation of CD8α dendritic cells which recruit CD8 T-cells and initiate strong anti-tumor responses. We have designed and developed potent classical small molecule (non-nucleoside) human STING agonists that activate all isoforms of human STING leading to robust secretion of Type I interferons and related cytokines. In order to increase the therapeutic index of our portfolio we have created modular sets of linkers and spacers to enable conjugation of our compounds to peptides and biomolecules. The first ADC with our lead STING agonist containing Trastuzumab as a carrier shows an impressive tumor to plasma exposure making it suited for intravenous delivery.

Metabolism

• The ACSS2 program focuses on the ability of tumors to survive in hostile microenvironments by altering their metabolic requirements. The inner tumor mass is a poorly vascularized, nutritionally barren hypoxic, hypoglycemic, hypolipidemic zone in which conventional cellular metabolism is dysregulated. However, certain tumor cells including cancer stem cells reprioritize the usage of internal metabolites and thrive in this environment. We have developed potent small molecule inhibitors of an enzyme that promotes tumor survival in these conditions. Combinations of these inhibitors with other forms of cancer therapy are being investigated to identify synergistic modes of tumor elimination.
• ACSS2 which plays a role in lipid metabolism could also be targeted in hepatic steatosis (PNAS, 2018). Targeting ACSS2 may provide a means of reducing lipid accretion without altering lean body mass.

Targeted Therapy

• The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma.  We demonstrated synergistic killing of human lymphoma cells by combining single agent inhibitors thus providing a rationale for the simultaneous inhibition of these pathways to achieve efficienttumor cell kill and overcome resistance to single agent use.  Medivation and Curadev then launched a program to identify dual inhibitors that would block both kinases.

Neuroinflammation

• Curadev has initiated a collaboration at INSERM’s Hôpital Robert Debré with Professor Pierre Gressens, a leading clinician researcher, who established that microglia driven neuroinflammation was the underlying cause of diverse neuropathologies including perinatal brain injury and white matter damage. This partnership places Curadev at the translational edge of academic research by providing us access to early discoveries on new pathways as well as current thinking in the field of neuro-immunology. Curadev will also have access to several central nervous system derived human and mouse cell lines as well as primary cultures and in-vivo disease models. For Curadev, this collaboration forms an important component of our early stage target identification program in the area of autoimmune diseases and cancers.