Our Science

Our Science
Our Science
Adapted from Brock & Huang, 2017 PMID: 29162615.

A Differentiated Approach to Targeting Treatment Resistant Cancer Cells

Conventional precision oncology is focused on profiling the genetics of a tumor to identify singular genetic alterations driving tumor growth.  However, tumors are characterized by complex genetic heterogeneity, with different genetic alterations driving the growth of distinct subpopulations of tumor cells, resulting in the inability of most conventional precision oncology therapies to eradicate all tumor cells.

To endure the harsh tumor microenvironment resulting from this uncontrolled, pathological cellular proliferation, and to escape destruction by the immune system, tumors activate adaptive stress response pathways mediating phenotypic switching which can result in treatment resistance, cancer relapse, and metastasis.

We are looking beyond traditional precision oncology to develop novel treatment options based on the modulation of specific adaptive stress response pathways.

Intrinsic and Extrinsic Stressors Associated with an
Adaptive Stress Response in Cancer


Targeted Therapeutics

Targeted Therapeutics

Targeted Therapeutics, such as VEGF/VEGFR inhibitors, can cause hypoxia and amino acid deprivation.

Chemotherapy

Chemotherapy

Chemotherapy can induce DNA damage and chromosome re-organization.

Radiation

Radiation

Radiation treatment can generate reactive oxygen species and cause DNA damage.

Metabolic Stressors

Metabolic Stressors

Metabolic stressors, including amino acid deprivation and lower pH.

Oncogenic Mutations

Oncogenic Mutations

Oncogenic mutations drive rapid cell division which results in a variety of stressors associated with dysregulated proliferation.


Potential for Improving on Standard of Care Precision Therapies

Intrinsic stress is common to many tumor types for which precision therapies are approved.  A number of therapeutic classes induce stress or can exacerbate the stress intrinsic to the tumor including, but not limited to, VEGF/VEGFR inhibitors, EGFR inhibitors, and inhibitors.  In working to modulate stress mitigating pathways with HC-5404 and HC-7366, we believe our therapeutic candidates have both monotherapy potential in tumors with high levels of intrinsic stress and the potential to improve patient responses in combination with standard of care therapeutics.

CD, cluster of differentiation; MDSC, myeloid-derived suppressor cell; PD-L1, programmed death ligand 1; Treg, regulatory T cell; VEGF, vascular endothelial growth factor. Joyce JA, Pollard JW. Nat Rev Cancer. 2009;9(4):239-252.

Overcoming Limitations of Current Immunotherapies

Endogenous and exogenous stressors also upregulate stress in immune cells, fostering an immunosuppressive tumor microenvironment that can restrict the benefit of current approved immunotherapies, including immune checkpoint inhibitors.  Most patients fail to benefit from checkpoint therapies because of one or more of the following:

  • Insufficient tumor antigens.
  • Poor antigen presentation.
  • Limited T cell trafficking and infiltration.
  • Limited T cell potential due to an immunosuppressive tumor microenvironment.

We believe that systemically activating the innate and adaptive immune systems with our investigational immune modulator, odetiglucan, has the potential to improve antigen presentation, T cell recruitment, T cell activation, alleviate immunosuppression in the tumor microenvironment and lead to robust anti-tumor responses in combination with immune checkpoint inhibitors.