Improving Quality of Life by Treating the Severe Side Effects of Targeted Treatments

Researchers from the Hebrew University and Hadassah Medical Center have developed highly effective treatment option designed to prevent skin toxicities induced by epidermal growth factor receptor (EGFR) inhibitors such as cetuximab (Erbitux®; Eli Lilly and Company) and panitumumab (Vectibix®; Amgen), used to treat many advanced-stage epithelial cancers.

EFGR, also known as ErbB-1 and Her1, is an enzyme that plays a key role in the cell signaling pathway, controlling cell division and cell survival. EGFR inhibitors induce severe skin toxicities in most treated patients. These side effects lead to a deterioration in the health related Quality of Life (hrQoL) of these patients,  In turn, as a result of these side effects, anti-cancer treatment can be compromised and current treatment strategies for these skin toxicities generally focus on symptom reduction rather than preventing the initial trigger that causes the toxicity.[1]

The results if a new study, lead by Sharon Merims, MD, Dermatology specialist and head of the dermato-oncology clinic, Hadassah Medical Center and Prof. Ofra Benny, MD of the School of Pharmacy, Hebrew University Jerusalem, were published in the journal Science Translational Medicine .[1]  The authors report on a new development that will relieve skin toxicity, improving patients’ quality of life during the challenging period of fighting the disease.

On-target and off-target
Current oncology treatments use on-target strategies that are meant to block a specific receptor on the tumor, leading to a delay in the cancer cells’ growth and a regression of the disease. However, because this specific receptor is also found in the healthy skin cells, skin toxicity is a known side effect of targeted cancer treatment.

In cancers like colon cancer and head and neck cancer, the treatment focuses on blocking a specific receptor for the EGFR pathway.  This pathway is critical for the growth and function of those cancerous cells, but it is also important for preserving healthy skin cells. The result is that while the targeted therapy will be effective in treating the cancer, 90% of the patients will develop skin toxicity with severe facial rashes that on top of the morbidity and discomfort caused by the rash, can influence the patients’ emotional well-being and may even impact their willingness to continue treatment.

The rashes caused by skin toxicity vary in location and appearance, but one of the most prominent features are severe facial rashes that severely damage patients’ health related Quality of Life – not only from the aesthetic point of view but also emotionally.  The location of the rashes on the face is like coming out with an announcement to the entire world that the person has cancer.

Unfortunately, there are no efficient treatment options available for these severe rashes.

Based on the outcomes of their study, Benny and Merims succeeded in developing a new cream whose active component is a drug that blocks the pathway of the cancer treatment drug to the EGFR receptor, preventing damage to the healthy skin cells but not impeding the cancer treatment.

Using computational modeling they identified, SDT-011, a potential drug candidate, that binds to the same EGFR receptors as the EGFR inhibitors.  A binding affinity assay demonstrated that, when SDT-011 was bound to EGFR, there was 2,000-fold reduction in the affinity of cetuximab and panitumumab.

One of the additional complexities the researchers faced is that that skin affected by toxicity is very difficult to penetrate. This creates a significant challenge to have a potential treatment reach deeper layers of the skin.

To solve this problem, the researchers relied on an earlier study that developed a special transmission mechanism using nano-molecules that deliver the drug to the hair follicles where most of the damage to the skin occurs.  The novel approach they developed enables ongoing treatment for a patient’s cancer, while, at the same time, limiting or neutralizing the damage caused by skin toxicities leading to rashes.

Using these results, the researchers developed a slow-release topical compound using nanoparticles designed to preferentially deliver SDT-011 to hair follicles.

Emotional distress
“Patients with severe skin toxicity affecting their face suffer greatly and their emotional distress is unique in that side effects are visible to everyone, as opposed to toxicities that affects internal organs that are invisible. Current treatments to prevent or reduce toxicity and rash are not effective. In most cases, the patient’s suffering is alleviated by reducing the dose of cancer treatment or stopping treatment altogether for a short time to help the skin recover and clear the rash. However, these actions may interfere with the treatment of the cancer,” Merims explained.

“This new drug [helps us to] continue treating the cancer, [ ] while, at the same time we can prevent the negative side effects of treatment. [This outcome] maintains a patients’ health related Quality of Life while they are being treated for the cancer,” Benny concluded.

Highlights of prescribing information
Cetuximab (Erbitux®; Eli Lilly and Company) [Prescribing Information]
Panitumumab (Vectibix®; Amgen)[Prescribing Information]

Reference
[1] Friedman N, Weinstein-Fudim L, Mostinski Y, Elia J, Cohen S, Steinberg E, Frankenburg S, Peretz T, Eisenberg G, Lotem M, Benny O, Merims S. Preventing skin toxicities induced by EGFR inhibitors by topically blocking drug-receptor interactions. Sci Transl Med. 2023 Jun 7;15(699):eabo0684. doi: 10.1126/scitranslmed.abo0684. Epub 2023 Jun 7. PMID: 37285403.