Pursuing New Frontiers in Oncology

Pursuing New Frontiers in Oncology

Pursuing New Frontiers in Oncology

A More Dynamic Approach to Targeting Resistant Cancer Cells

Precision oncology is focused on profiling the genetics of a tumor to identify actionable mechanisms driving cancer at the molecular level. This approach has provided some patients with significant benefit, but phenotypic switching driven by the adaptive stress response contributes to tumor survival in some patients, which can ultimately lead to treatment resistance, cancer relapse, and metastasis.

We are looking beyond traditional precision oncology to understand how best to treat these cells, which survive due to activation of the adaptive stress response. Armed with these insights, our goal is to provide differentiated treatment options that eliminate these resistant cancer cells via targeting and modulation of adaptive stress.

How Cancer Leverages the Adaptive Stress Response to Escape Current Therapies

Most tumors are characterized by considerable genetic heterogeneity. This suggests that not all the cells are supported by the same genetic driver even within a single tumor. A common outcome of this is that genetically-targeted therapies will not be able to eradicate all cancer cells. As a result, tumors have numerous mechanisms to survive a variety of standard-of-care treatments.

We believe cancer cells that trigger the adaptive stress response contribute to a more aggressive cancer cell phenotype that can drive disease progression.

 

 

Characteristics of Cancer Survivor Cells

Immunologically invisible (decreased MHCII expression)

Decreased proliferation

Protective autophagy

Ability to resist damage from low pH and ROS

Adaptive Stress is the Achilles’ Heel of Cancer Survival

The adaptive stress response is triggered by genetic alterations, physiologic stressors, and standard-of-care therapies. Adaptive stress activation via UPR and ISR reprograms cancer cells to survive, while creating an immunosuppressive tumor immune microenvironment. Collectively, this allows tumors to become treatment resistant and can eventually lead to cancer relapse and metastasis.

In preclinical studies, we have observed that blunting the adaptive stress response via PERK and GCN2 modulation can eliminate cells that would otherwise be resistant to therapy. Additionally, by reprogramming the innate immune system, we can overcome the immunosuppressive immune environment inspired by the adaptive stress response.

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

Our Novel Therapeutic Programs Address Key Elements of Treatment Resistance and Effective Anti-Cancer Immunity


Overcoming the Adaptive                                              Stress Response

Stress Modulation

Our first two adaptive stress modulators target the PERK and GCN2 kinases. These kinases are key mediators of the adaptive stress response and facilitate cancer cell survival and immune suppression.

Overcoming the Immunosuppressive
Tumor Microenvironment

Immune Activation

We have observed in preclinical studies that our innate and adaptive immune modulator agonizes Dectin-1, which primes a de novo T Cell immune response, reprograms the immunosuppressive tumor microenvironment and induces trained innate immunity, which collectively, can lead to a more durable anti-tumor immune response.