Nucleotide-excision Repair

1. Disease Summary:

Nucleotide excision repair (NER) is a critical DNA repair mechanism that removes a wide range of DNA lesions, particularly those caused by ultraviolet (UV) light and various environmental toxins. Deficiencies in the NER pathway can lead to a variety of genetic disorders, most notably Xeroderma Pigmentosum (XP), which is characterized by extreme sensitivity to UV radiation, resulting in a significantly increased risk of skin cancers. Other conditions associated with NER deficiencies include Cockayne syndrome and Trichothiodystrophy. These disorders highlight the importance of NER in maintaining genomic stability and preventing cancer.

2. Global Prevalence and Disease Burden:

The global prevalence of NER-related disorders varies, with Xeroderma Pigmentosum affecting approximately 1 in 1 million individuals in the United States and Europe, but higher rates are observed in certain populations, such as in Japan and North Africa. The disease burden is significant, as individuals with XP face a lifetime risk of skin cancer exceeding 50% by age 20. The economic impact includes increased healthcare costs for cancer treatment, management of skin lesions, and the need for protective measures against UV exposure. The psychological burden of living with a chronic condition that significantly increases cancer risk also contributes to the overall disease burden.

3. Unmet Medical Need:

Despite advancements in understanding NER and its role in cancer, there are several unmet medical needs:

Predictive Biomarkers: Current methods to predict patient responses to platinum-based chemotherapy, which relies on NER, are inadequate. Although studies have shown correlations between NER protein expression and treatment response, these findings have not been effectively translated into clinical practice (Bowden NA, PMID: 24462818). This gap limits the ability to tailor treatments based on individual patient profiles.
Effective Therapies for NER Deficiencies: Patients with NER deficiencies often exhibit resistance to standard therapies, including platinum-based agents like cisplatin. The lack of effective alternative therapies for these patients represents a significant unmet need. Current treatments primarily focus on managing symptoms and preventing skin cancers rather than addressing the underlying DNA repair deficiencies.
Research Gaps: There is a need for more comprehensive research into the mechanisms of NER-related cancers and the development of targeted therapies. Current clinical trials are limited in scope and do not adequately address the diverse genetic backgrounds of patients with NER deficiencies (Leung AK et al., PMID: 35520754).

4. Current Treatment Options:

Current treatment options for NER-related disorders include:

Preventive Measures: For conditions like XP, strict sun avoidance and the use of high-SPF sunscreens are critical to prevent skin damage and cancer. Regular dermatological check-ups are essential for early detection of skin lesions.
Surgical Interventions: Treatments for actinic keratosis and skin cancers include cryotherapy, topical chemotherapy (e.g., 5-fluorouracil), and surgical excision. However, these treatments do not address the underlying NER deficiency and are reactive rather than preventive.
Emerging Therapies: Investigational therapies such as T4 endonuclease-V liposome lotion and oral nicotinamide are being explored to enhance DNA repair mechanisms and reduce skin cancer incidence (Leung AK et al., PMID: 35520754). However, these therapies are not yet widely available or validated in clinical practice.

5. Current Clinical Trials:

Several clinical trials are currently investigating novel therapies targeting NER deficiencies. For example, trials are exploring the efficacy of PARP inhibitors in cancers with defective DNA repair mechanisms, including those involving NER (Fugger K et al., PMID: 34563478). However, the results of these trials are still pending, and there is a need for more focused studies on NER-related cancers.

6. Additional Context:

The economic impact of NER-related disorders is substantial, encompassing direct healthcare costs for cancer treatment and management, as well as indirect costs related to lost productivity and the psychological burden on patients and families. The need for improved predictive biomarkers and targeted therapies is critical to enhance patient outcomes and reduce the overall burden of NER-related diseases.