Why is interest in hypoxia re-ignited?

25 Mar Why is interest in hypoxia re-ignited?

In this news, we would like to break down how hypoxia fuels cancer, why past attempts to target it failed, and how we’re working to turn hypoxia into a weapon against itself.

Part 1: Tumor Hypoxia – The “Stealth Mode” of Cancer

Tumor hypoxia refers to low oxygen levels in parts of a tumor, a condition that affects over 9 million patients annually (45% of cancers). Hypoxia creates a hostile environment that resists conventional cancer treatments:

• Radiation Therapy: Requires oxygen to generate DNA-damaging free radicals. Without oxygen, radiation becomes less effective.
• Chemotherapy: Relies on active cell death mechanisms that hypoxia disrupts.
• Immunotherapy: Hypoxia weakens immune responses and creates a protective shield for tumors.

Despite its challenges, hypoxia also presents opportunities for innovative treatments.

Part 2: Metabolic Shifts in Hypoxic Tumors

Hypoxia drives metabolic reprogramming in cancer cells, enhancing their survival, proliferation, invasion, and resistance to therapy. Key mechanisms include:

1. Enhanced Glycolysis: In low-oxygen environments, cancer cells shift from oxygen-dependent oxidative phosphorylation (OXPHOS) to glycolysis for ATP production. Although glycolysis is less efficient (2 ATP vs. ~36 ATP per glucose molecule), it operates faster, meeting immediate energy demands (Semenza, 2012).
2. Acidic Microenvironment: Lactate accumulation from glycolysis acidifies the tumor microenvironment (TME), which:
   • Breaks down the extracellular matrix (ECM), facilitating invasion and metastasis.
   • Suppresses immune responses by impairing T-cell and natural killer (NK) cell function.
   • Selects for aggressive tumor clones that thrive under harsh conditions (Rankin & Giaccia, 2016).
3. Angiogenesis: Hypoxic tumors stimulate new blood vessel formation through vascular endothelial growth factor (VEGF) expression, driven by hypoxia-inducible factor 1-alpha (HIF-1α). However, this vasculature is often dysfunctional, perpetuating chronic hypoxia (Semenza, 2012).

These adaptations make hypoxic metabolism a critical driver of tumor progression and therapy resistance.

Part 3: Hypoxia and Immunotherapy Challenges

Hypoxia also undermines immunotherapy by creating an environment hostile to immune cells:

• T-cell Exhaustion: Oxygen-starved environments weaken T-cells by creating metabolically hostile conditions. Lactate buildup further impairs their function.
• Immunosuppressive Environment: Hypoxia increases regulatory T-cells (Tregs) and fosters immunosuppressive factors like ADP, IL-10, PD-L1, VEGF, TGF-β, and myeloid-derived suppressor cells (MDSCs).
• Immune Checkpoint Resistance: Hypoxia upregulates PD-L1 expression on cancer cells, reducing the effectiveness of immune checkpoint inhibitors like Pembrolizumab (Keytruda). It also alters the ECM, blocking immune infiltration.

Poor blood supply in hypoxic tumors restricts antibody delivery and immune cell penetration, further limiting immunotherapy’s effectiveness.

Part 4: Hypoxia-Activated Prodrugs – Turning the Tables

Hypoxia-activated prodrugs (HAPs) offer a promising solution by exploiting tumor hypoxia as a therapeutic target:

• Mechanism: HAPs remain inactive in healthy tissues but selectively activate in severely hypoxic tumors.
• Analogy: Like heat-seeking missiles homing in on their targets’ heat signatures, HAPs use the tumor’s own characteristics—its hypoxic zones—as a guide.
• Examples: Convert Pharmaceuticals develops drugs like CP506 and Tarloxotinib that activate only in low-oxygen environments. These therapies aim to overcome treatment resistance by targeting cancer cells where they are most vulnerable.

Preclinical data show that combining HAPs with existing therapies can potentially overcome resistance without overlapping toxicities. Immunohistochemical staining with pimonidazole and EF5 has demonstrated CP506’s hypoxia selectivity and cytotoxicity.

Part 5: Why past attempts failed

• Absence of patient selection

The presence of hypoxia is a prerequisite for the activation of hypoxia-activated prodrugs, occurring in 50% of all solid tumors (9m patients/year!). But early-generation HAPs lacked robust biomarkers to select patients with hypoxia. As a result, clinical outcomes were mixed, highlighting the need for precise patient selection. A modeling study has demonstrated that a biomarker-driven approach would increase the likelihood of a positive trial even if the biomarker is “not perfect” (doi: 10.1016/j.ctro.2019.01.005).

• Unreliable activation

Many first-gen HAPs failed because they didn’t activate reliably in tumors. Some drugs activated in the bone marrow, others activated too with moderate hypoxia present in normal tissues.

• Last-minute changes in formulation

Several promising HAPs were modified late in development, affecting their bioavailability and pharmacokinetics. Reformulations led to lower PK reducing efficacy and unpredictable side effects (doi:10.1172/jci.insight.122204).

Great science is built upon the past attempts of other bright scientists, so helped with their learnings we believe CP506 will be the first HAP to market. Our first patient received CP-506 and early results are promising.

References

For readers interested in exploring this topic further, here are some key references cited in this post:

Rosenblum et al., Nat Commun, 2018: https://doi.org/10.1038/s41467-018-03705-y

Brown & Wilson, Nat Rev Cancer, 2004: https://doi.org/10.1038/nrc1367

Vaupel et al., Cancer Metastasis Rev, 2007: https://doi.org/10.1007/s10555-007-9055-x

Corzo et al., J Exp Med, 2010: https://doi.org/10.1084/jem.20091474

Sceneay et al., Oncoimmunology, 2013: https://doi.org/10.4161/onci.23175

Gray et al., Br J Radiol, 1953: https://doi.org/10.1259/0007-1285-26-312-638

Wilson & Hay, Nat Rev Cancer, 2011: https://doi.org/10.1038/nrc2984