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YAG-1 Cancer Photodynamic Therapy

1. What is Skin Cancer?

2. Types of Skin Cancer

3. Photodynamic Therapy

4. YAG-1 Photodynamic Therapy

What is Skin Cancer?
Skin cancer is a collective term for a large variety of conditions, ranging from the aesthetically unpleasant to the life-threatening, which share the basic property of being composed of cells whose proliferation is not under normal body control.
The skin is the body's largest organ, covering a surface of about 2 square meters on an adult body. Its very nature of "body interface" to the outside world makes it particularly vulnerable to damaging agents such as sunlight, chemicals, smog, bacteria and viruses.
Although the human skin is particularly well designed at managing the damage suffered on a daily basis, as for any other organ, things may go wrong and some cells end up accumulating a series of DNA damage hits known as mutations. Most mutations are anyway harmless or lead to the death of the mutated cell, and therefore self-destructive. As time goes by, however, one cell may undergo just the right kind and number of mutations to become rapidly proliferating, insensitive to the body's restraining signals and invasive toward surrounding tissue. These cells are called malignant and the resulting, abnormal tissue a tumour. The figure below shows this process in action to produce a type of skin cancer (melanoma)

A diagram of normal versus cancer (melanoma) affected skin

What types of skin cancer are there?

The skin is a large and complex organ made of many different components like the epidermis, the dermis, hair follicles, melanocytes and others. Therefore there is a whole range of "skin" tissue deregulated growth (hyperplasias). The most common are:

Basal cell carcinoma (BCC): It is also called Rodent Ulcer and it is thought to originate from hair follicle keratinocytes.It is the most common with over 50,000 cases diagnosed each year in the UK alone. Fortunately, it is slow growing and rarely spreads to other body sites.

Squamous cell carcinoma (SCC): It is the second most common. It still originates from keratinocytes of the epidermis but it is more aggressive than BCC, even though less so than melanoma. It can spread to other body sites and cause death if left untreated.
Melanoma (SCC): It is by far the most dangerous skin cancer even though far less common than the previous ones (about 6,000 cases per year in the UK). It arises from melanocytes, the skin cells responsible for skin color and suntan. It grows rapidly, spreads readily down into the dermis and propagates to other organs posing a serious death risk. It is so stealthy that sometimes body spreads (metastases) are noticed before the actual primary tumour is reported.

Examples of a BCC, an SCC and a melanoma

What is Photodynamic Therapy?

Until recently the only option to treat skin cancers was surgery followed or not by chemotherapy. For melanoma, it is still the only viable option. But surgery has its drawbacks: it is an invasive technique, it requires a hospital, it can leave scars which are particularly unpleasant is on the face.
Photodynamic therapy is a relatively (20 years) new technique which can be described as "light activated chemotherapy". It is based on the local or systemic delivery of a compound called photosensitizer which penetrates all the cells in the area but shows a preference for cancer cells. A photosensitizer is a chemical compound, of the family of Porphyrins, that can be excited by light of a specific wavelength. In classical PDT this excitation uses visible or near-infrared light. The photosensiizer, activated by the light only where it is applied (the tumour lesion), will react with oxygen turning it into a very reactive species called "singlet oxygen". This molecule is "corrosive" to chemicals inside the cells and causes its death.
What are the drawbacks of classical PDT? Ideally, only cancer cells should be hit but because the compound penetrates all cells to some extent, the risk of burns and pain is always present, specially on the skin. Moreover, the sensitivity of the drug to visible red light puts the patient at risk when leaving the clinic, therefore it is often necessary to operate confinement for some time.

What is YAG-1 Photodynamic Therapy?

We have found a novel, non proprietary drug whose effectiveness on cells has been extensively characterized for many years. This research was mainly carried out by Prof. Peter Karran at CRUK and Dr Yao Xu at the Open University. This molecule is a nucleotide analog, which means it looks like and mimics the chemical behaviour of a nucleotide, a building block of DNA. As such, it is incorporated in cells as part of their metabolism.However, not all cells will absorb it but only those which need DNA, i.e. the ones which actively proliferate. This way, cancer cells are likely to specifically absorb the drug in far greater amounts than bystanders such as nerve cells or keratinocytes. Thus, the molecule is far more cancer specific than current PDT photosensitizers.
In addition to this property, the molecule has the distinctive capacity to absorb light at a wavelength where normal nucleotides don't, i.e. UV-A light. Normal nucleotides absorb in the higher energy UV-B region, and this is the reason why UV-B can damage DNA and we need to protect ourselves from it. UV-A on the other hand is safe and used in tanning salons worldwide.
These two properties combined result in the molecule conferring DNA damage sensitivity only to cancer cells while sparing normal surrounding cells, therefore making a superior photosensitizer.
We have drawn from this scientific research and used the basic molecule as a starting point, to synthesize a drug with superior tumour localizing capacity and bioavailability. This has resulted in a medicine for the treatment of skin cancers and hyperplasias in general. We have labelled this compound YAG-1 and tested its effectiveness in our labs on real tumour tissue samples

YAG-1: The scientific evidence

We have tested YAG-1 in our labs on various skin cancer cell types and SCC and BCC tissue biopsies provided by our clinical associates.Below are some of the results obtained.
Efficacy on cells We confirmed the extraordinary power of the drug on cell cultures extracted from the most common and dangerous cancers, skin and more. This is the effect of a single application of the drug on melanoma cells, followed by irradiation of UV-A at 10kJ/m²

YAG-1 on melanoma cells: left, no UV light; right, UV light

YAG-1 on SCC cells. Blue: all cell counterstain; Green: apoptotic (dead) cells

Similar results were obtained on breast, prostate and lung cancer cells.
Next, we assessed the efficacy of YAG-1 on actual SCC and BCC biopsies from excision surgery operations. We applied the drug on the skin like it would be done on a patient, let it penetrate, then irradiated with UV-A light as before.This is an example of the results we obtained on SCC and BCC tumours

YAG-1 application on an BCC tissue biopsy. Blue=all cells: Green:apoptotic cells

YAG-1 application on an SCC tissue biopsy. Blue=all cells: Green:apoptotic cells

The success in treating tumour models (biopsies) was complete on all the samples tested. Moreover, applications on normal keratinocytes (healthy skin) biopsies confirmed that no toxicity on normal cells is observed, as expected.

YAG-1 application on facelift (normal) skin. Blue=all cells; Green=apoptotic cells

YAG-1 has been tested also on non malignant skin disorders such as keloids. These are abnormal scars which cause disfiguring lumps on the skin which often need resection; however, any surgery will lead to a wound and possibly a recurrence of the keloid. The benefit of a topical treatment which is not invasive and does not pose risks of keloid recurrence is here obvious. The results (below) show that cells in the hypertrophic keloid tissue are selectively destroyed, thus proving that any form of cellular hyperplasia is amenable to treatment with our product

Effectiveness of YAG-1 against Keloid tissue

YAG-1: Current Status of Drug Development

The next step in lab experiments is the testing on melanoma biopsies, which are much harder to come across given the need for immediate histology analysis.
By virtue of the exceedingly good results obtained in the lab, Yagna has decided to take YAG-1 to Phase I clinical trials. We are currently in the process of seeking MHRA approval for the trial, which will hopefully start some time later this year.
The YAG-1 technology is covered by two patents currently in the PCT stage and we plan to go into national phases at the end of this year.
We are also designing new molecules with the aim of improving the potency of the drug and the IP value of our product. We are presently seeking the cooperation of academic institutions to launch joint research programmes in this direction.