Engineered Heme Sequestering Peptides for Cancer Therapy
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Solution Overview
Problem
Current treatments for non-small cell lung cancer (NSCLC) are ineffective, with low five-year survival rates, and there is a need for novel therapeutic strategies due to the elevated heme uptake and mitochondrial heme levels in NSCLC cells, which contribute to their tumorigenic functions and drug resistance.
Innovation Solution
Development of recombinant heme sequestering peptides (HeSPs) that bind to heme with high affinity, reducing its availability to NSCLC cells, which are engineered to have neutral amino acid substitutions, fusion sequences from distinct heme binding proteins, or truncations to minimize immunogenicity, and are designed to sequester heme from biological environments, including cancer cells and pathogenic fungi.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for NSCLC, then treatment is provided, but survival rate remains low (10-20% five-year survival)
Solution Approach 1:
The patent converts the harmful overexpression of heme uptake proteins in NSCLC cells into a therapeutic advantage by using engineered hemophores to selectively sequester heme from these cells. The high heme uptake capability that drives tumor growth is exploited to deliver therapeutic heme deprivation specifically to cancer cells while sparing normal cells.
Solution Approach 2:
The patent introduces engineered hemophores as intermediary molecules that mediate heme sequestration between the biological environment and NSCLC cells. These hemophores act as heme scavengers that compete with cancer cells for heme, thereby reducing heme availability to tumor cells without directly interacting with cellular machinery.
2Productivity
If heme uptake proteins are overexpressed in NSCLC cells, then tumorigenic functions are potentiated, but this creates a targetable vulnerability
Solution Approach 1:
The patent applies preliminary anti-action by pre-engineering hemophores with enhanced heme-binding capabilities before administering them to patients. These pre-modified hemophores are designed to outcompete endogenous heme uptake proteins, establishing heme deprivation in NSCLC cells before the cancer can utilize heme for tumorigenic functions.
Solution Approach 2:
The patent modifies key parameters of hemophores including amino acid substitutions in heme-binding pockets, fusion of heme-binding domains from distinct proteins, and truncations to reduce immunogenicity. These parameter changes enhance heme-binding affinity while minimizing immune response, creating optimized therapeutic agents.
3Productivity
If heme is sequestered from NSCLC cells, then tumor growth is suppressed, but heme is essential for normal cell function
Solution Approach 1:
The patent applies local quality by creating heterogeneous heme availability across different cell types. Engineered hemophores selectively deplete heme in NSCLC cells that overexpress heme uptake proteins, while normal cells with baseline heme uptake maintain sufficient heme levels for physiological functions. This localized heme deprivation spares normal tissue while targeting cancer cells.
Solution Approach 2:
The patent uses partial action by administering hemophores at doses and concentrations that achieve sufficient heme sequestration in NSCLC cells without completely depleting heme from the entire biological system. This partial heme deprivation is adequate to suppress tumor growth while maintaining essential heme functions in normal cells.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The HeSPs effectively inhibit heme uptake in NSCLC cells, reduce mitochondrial heme levels, suppress tumor growth, and inhibit proliferation and biofilm formation in Candida albicans, demonstrating their potential as a therapeutic strategy for cancer and microbial diseases by lowering heme supply.
Implementation Method 1
bind to heme with very high affinity (Kd=18 pM)
Data Source
AI summary
The disclosure relates to engineered heme sequestering peptides and their use in treating cancer and inhibiting microbial infections and colonization.