Mechanism of Action

EGFRI INDUCED RASH

EGFR (Epidermal Growth Factor Receptor) is a receptor on the surface of cells which is expressed in many normal epithelial tissues, including skin. The EGFR signaling pathway is one of the most important pathways that regulate growth, survival, proliferation, and differentiation of cells. B-Raf is protein encoded by the BRAF gene and is a downstream effector component of EGFR signaling pathway. EGFR is shown to be over-activated in various human cancers, including colorectal, lung, head & neck, urinary bladder, pancreatic and breast, cancers. While over-activated, it elicits downstream phosphorylation and activation of the MAP Kinase pathway and B-Raf protein.

Drugs called EGFR inhibitors can block the EGFR signal responsible for cell growth. Among the various types of pharmacological therapies for cancer, EGFR inhibitors are increasingly being used both as primary therapy as well as in patients who have failed prior chemotherapy. Although effective as anti-cancer therapy leading to tumor shrinkage, EGFR Inhibitors have a number of adverse reactions associated with their use. The majority of patients treated with EGFR Inhibitors will experience dermatological side effects typically manifested as a papulopustular skin rash, also known as acneiform lesions, which can impact quality of life and affect adherence to therapy.

BRAF gene was shown to be mutated in some human cancers such as melanoma cancer. Since then, B-Raf Inhibitors have been developed and used for the treatment of some B-Raf–mutated cancers. Blocking the B-Raf pathway (downstream of EGFR pathway) in B-Raf mutated cells, indeed, stop them from growing and lead to tumor shrinkage. However, when the same pathway was blocked in wild-type (without mutation) cells, the opposite happens, the MAP Kinase pathway is activated and cells start growing. This phenomenon is recognized as the paradoxical effect of B-Raf Inhibitors.

LUT014, Lutris- Pharma lead compound, is a novel B-Raf inhibitor which is applied topically on the skin. The technology is based on harnessing the paradoxical effect of B-Raf Inhibitors on wild type epithelial cells thus overriding MAP Kinase pathway inhibition.  By reversing the inhibitory effect of EGFR inhibitors on downstream proteins in the skin cells, LUT014 is developed to reduce dose-limiting acneiform lesions associated EGFR Inhibitors treatment.

RADIATION DERMATITIS

Optimal treatment of many cancer types such as breast cancer usually requires a combination of therapies and radiation therapy. Radiation therapy results in ionization events that lead to damage of cellular macromolecules, including double-stranded DNA breaks.  Within the epidermis, this DNA damage disrupts the normal proliferation and differentiation of basal keratinocytes, depleting the differentiated epidermal keratinocytes and ultimately resulting in the loss of the protective barrier provided by the skin.  This combined with DNA damage disruption within the dermis, which results in a complex set of effects including an immune response cascade, leads to the symptomology associated with radiation dermatitis.

The epidermis is comprised primarily of keratinocytes  and undergoes a continual process of proliferative self-renewal.  Studies suggest that this proliferative self-renewal process relies, in part, on continual signals for cell division and survival transmitted by the MAPK (ERK1/2) signalling pathway, and that tight regulation of this pathway plays a role in the control of normal skin development and homeostasis.

Lutris Pharma hypothesizes that the paradoxical activity of a B-Raf inhibitor can be leveraged in the setting of acute radiation dermatitis, where temporary hyperproliferation is desirable to repopulate the epidermal keratinocytes and restore the skin barrier.  Specifically, topical application of LUT014 to radiation-induced dermatitis will stimulate proliferation of the basal keratinocytes, driving the repopulation of the epidermal keratinocytes, and improving upon the time to dermatitis resolution.

Lutris Pharma  is developing LUT014 for the treatment of radiation-induced dermatitis in breast cancer patients, as the first indication in this field. There is currently no FDA-approved drug whose labelled indication is for the prevention or treatment of radiation-induced dermatitis.  Rather, patients are merely treated with supportive cutaneous care.  These treatments have included topical steroids, non-steroidal anti-inflammatory topicals, and hyaluronic acid derivatives.  To date, none has been definitively proved efficacious.  To that end, this indication represents an unmet medical need.