About Adaptive Stress

Characteristics of Cancer Survivor Cells

Immunologically invisible (decreased MHCII expression)

Decreased proliferation

Protective autophagy

Ability to resist damage from low pH and ROS

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.

In order 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.

Adapted from Brock & Huang, 2017 PMID: 29162615.

Adaptive Stress is the Achilles’ Heel of Cancer Survival

A tumor microenvironment is characterized by a broad range of intrinsic and extrinsic stressors, including genetic alterations, physiological perturbations and exposure to anti-cancer treatments (radiation, chemotherapy, and targeted therapeutics).

Cancer cells activate adaptive stress response pathways in order to enable their survival and continued proliferation under these stressful conditions.

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

Targeted Therapeutics

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

Chemotherapy

Chemotherapy can induce DNA damage and chromosome re-organization.

Radiation

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

Metabolic Stressors

Metabolic stressors, including amino acid deprivation and lower pH.

Oncogenic Mutations

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

Working to Overcome the Adaptive Stress Response: the HiberCell Approach

Adaptive stress responses via activation of the UPR and ISR pathways can reprogram cancer cells to survive, while creating an immunosuppressive tumor microenvironment. Collectively, this can allow tumors to become treatment resistant and can eventually lead to cancer relapse and metastasis.

In preclinical studies, we have observed that modulating two critical kinases, PERK within the UPR pathway and GCN2 within the ISR pathway, can eliminate tumor cells that would otherwise become resistant to therapy. Additionally, by reprogramming the innate immune system, we may be able to overcome the immunosuppressive immune environment inspired by the adaptive stress response.

We believe that targeting the adaptive stress response has the potential to drive more meaningful efficacy and enable more durable responses to therapy.