Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome or Basal Cell Nevus Syndrome (BCNS), is a hereditary condition characterized by a wide range of developmental abnormalities and a predisposition to neoplasms. It is caused by mutations in the PTCH1 gene and is transmitted as an autosomal dominant trait with complete penetrance and variable expressivity.
The estimated prevalence varies from 1/57,000 to 1/256,000, with a male-to-female ratio of 1:1.
Main clinical manifestations include multiple basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, hyperkeratosis of palms and soles, skeletal abnormalities, intracranial ectopic calcifications, and facial dysmorphism (macrocephaly, cleft lip/palate and severe eye anomalies). Intellectual deficit is present in up to 5% of cases.
BCCs are a prominent feature of BCNS and occur at an earlier age than sporadic BCCs. BCCs may arise in various stages of the syndrome: most often they appear between puberty and 35 years of age, but cases have been reported in 3 or 4 year-old patients; in general, the mean age of onset is about 25 years of age.
The number of BCCs varies from a few to several thousand. The size of BCC lesions varies from 1 mm to 10 mm. Although more common in sun-exposed areas, they can occur anywhere, and tend to be more aggressive than sporadic BCCs. Nevertheless, local invasion or metastatic spread is uncommon, but because of the large number of lesions, treatment of BCCs in affected patients may be extremely difficult. Surgery for BCCs is indicated when the number of lesions is limited; other treatments include laser ablation, photodynamic therapy and topical chemotherapy. Radiotherapy should be avoided.
Multiple surgical procedures are a source of discomfort, pain and disfigurement, and thus alternative, less invasive treatment options are needed.
Ascend is developing ASN-002 in combination with chemotherapy as a safe and effective non-surgical treatment option of BCCs in patients with BCNS. ASN-002 is based on a replication deficient adenovirus type 5 (Ad5 is a type of common cold virus) engineered to express interferon – a potent protein that can stimulate the immune system to destroy cancers. ASN-002 has synergetic effect with chemotherapy that enhances anti-tumour effect of chemotherapy, and also produces both Interferon alpha (IFNα) and Interferon gamma (IFNγ) upon injection into skin cancers.
The interferon family of proteins has been previously shown to be effective in treating basal cell carcinoma when injected as a recombinant protein. However, recombinant protein rapidly leaks from the tumour site into the blood, necessitating frequent injections that results in greater side effects. In contrast, ASN-002 has the ability to overcome this deficiency by enabling a sustained local production of the protein contained primarily within the tumor site, thus reducing the frequency of injections required and the systemic adverse events. Because Interferon-γ receptors are expressed on most cells in the body, the local level IFNγ released by ASN-002 within the tumor would provide a local effect without causing systemic toxicities. In addition, by confining IFNγ to be expressed locally within the lesions, the chemokines induced by this cytokine would be more effective in selectively recruiting inflammatory cells to the tumor environment (this selective recruitment may be diminished when cytokines are over-expressed).
Further information for patients