top of page

The New Discovery

A New Pathway to Cancer Cure

Diagram2.png
The amino acid sequence above had not previously been recognised.
  • What has only been discovered in the past few years is that the cell cyclin control protein cyclin dependent kinase 4 (Cdk4)  may play an important role in helping cancer cells avoid apoptosis.

 

  • Cdk4 is normally responsible for starting cell division by joining with cyclin D. This activates Cdk4 phosphorylation of the Rb protein which then switches on the proteins responsible for doubling DNA.

 

  • Cdk4 has another previously unrecognised activity as well as its well-known kinase function, however.

 

  • I discovered that Cdk4 transfected into breast epithelial cells caused the elevation Cdk1 (which controls the final stage of cell division into two daughter cells) without also phosphorylating pRb.

 

  • This led me to identify a different region of Cdk4 from the well- known phosphorylation (kinase) site. It was on an external loop at the C'-terminal end of the molecule which I called the non-kinase region (NKR).

Cdk4 Protein

N' Terminus

C' Terminus

KINASE
NKR

Necrosis

  • The non-kinase region was found to carry the six amino acid sequence PRGPRP (Pro-Arg-Gly-Pro-Arg-Pro).

 

  • The sequence PRGPRP was inserted into a construct (a cyclic amphiphilic peptide) to carry it in high concentration into cancer cells.

 

  • In much higher concentration than when it was in an external loop of Cdk4, PRGPRP caused a fall in the energy molecule ATP and the cancer cells died by necrosis.

Screenshot 2023-04-12 at 14.39.55.png
Insufficient energy to run vital cell function:
Failure of pumps result in leaky cell membrane
Cancer cells of many different types of cancer were all killed by the same dose of PRGPRP in a similar way.
PRGPRP selectively killed cancer cells but not normal fibroblast or epithelial cells (keratinocytes).
Peptide comparison2.png

Development of a Lead Compound

  • Over the last decade modifications have been made to PRGPRP (the warhead) and its cyclic amphiphilic cassette, producing HILR agents with high enough specific activity to work clinically.

 

  • The new analogues are relatively insoluble in water and require delivery by the proprietary agent Nanocin (Tecrea Ltd) to  increase water solubility. Nanocin may also improve cancer cell uptake as shown by autofluorescence of one of  the new warhead components.

​

  • The new warheads include highly polar (non-water soluble) amino acid side chains which should also make them resistant to proteolysis.

Bright Field
Fluorescence

Mechanism of Action

  • Based on our own investigative experiments and an extensive literature review, we believe that cancer cells avoid apoptosis by switching off mitochondrial respiration.

 

  • This explains the importance of sugar metabolism first described by the Nobel Laureate, Otto Heinrich Warburg nearly a century ago.

 

  • The resulting state of aerobic glycolysis is mediated by the pyruvate kinase isoenzyme PKM2 which is transcribed from the pyruvate kinase gene using exon 10 rather than exon 9. This leads to an amino acid sequence in the pyruvate kinase enzyme which is unique to cancer cells.

​

  • Within this region I have identified an amino acid sequence (SDPTEA) that matches the warhead of PRGPRP selective cancer killing peptides.

PKM2 uses Exon 10 (white) rather than Exon 9 (black)

Cancer Cells Avoid Apoptosis By Modulating Aerobic Glycolysis

  • DNA Damage can result in oncogenic mutations that drive Cell Division by upregulating Cdk4.
     

  • In normal cells oncogenic DNA Damage that cannot be repaired causes Apoptosis. 

​

  • In Cancer cells which express PKM2, the NKR region of Cdk4 down-regulates PKM2, lowers ATP and prevents apoptosis.

​

  • This explains why the presence of normal CDK4 is needed for malignant transformation to be successful.

Diagram1.jpg

PRGPRP Peptides Hijack The Way Cancer Cells Avoid Apoptosis And Kill Them By Necrosis 

  • HILR-056 is a highly effective free cyclic amphiphilic modified peptide copy of CDK4-NKR

​

  • HILR-056 mimics the effect of CDK4-NKR on the cancer-specific region of PKM2

​

  • HILR-056 strongly inhibits PKM2, depletes cancer cell ATP and kills the cancer by necrosis

​

  • HILR-056 does not affect normal cells which have PKMI not PKM2

​

  • HILR-056 could be the first example of a truly selective global treatment for cancer.

Diagrams2.jpg

An Attempted Simple Explanation

If normal cells get mutations that cause malignant transformation they commit suicide.

​

To commit suicide needs energy. You have to put the chair in place attach the noose to somewhere on the ceiling, climb up on the chair put the noose around your neck and finally kick the chair away.

​

Cancer cells accumulate masses of oncogenic mistakes but they avoid suicide by turning down the level of the key energy supplying molecule (ATP) so they are unable to even make sufficient effort to kill themselves.

 

I have worked out how cancer cells do this and hijacked that mechanism. But what I do causes the energy supply to be turned down much further than the cancer cells really want.

 

They run out of energy. The pumps that keep excess water out of the inside of the cell fail and the cancer cell drowns.

 

In a manner of speaking - I come alongside the cancer cells as a supposed friend and pretend to help them avoid suicide.

​

I whisper to them "I understand what you are doing. I can help you reduce your energy levels and live". " Thank you say the cancer cells that is extremely kind of you". (Little do they know that cancer shouldn't trust an oncologist.)

​

I've found and developed over 20 years, a drug that works in this way. It kills all different types of cancer and does not seem to damage normal cells. If it worked in this way in the clinic the impact could be huge.

bottom of page