Skin cancers
Skin cancers (i.e., basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma belong to the most frequent tumors. Their formation is based on constitutional and/or inherited factors usually combined with envirnomental facts, mainly UV-irradiation through long term sun exposure. UV light can randomly induce DNA damage in keratinocytes, but it can also mutate genes essential for control and surviellance in the skin epidermis. Various repair mechanisms exist. For example, DNA damaged cells are eliminated by apoptosis (sunburn cells). This occurs under the control of the p53 suppressor gene. Fas-ligand (FasL), a member of the tumor necrosis superfamily, which is preferentially expressed in the basal layer of the skin epidermis, is a key surveillance molecule involved in the elimination of sunburn cells. However, UV light exposure downregulates FasL expression in keratinocytes and melanocytes leading to the loss of its sensor function. Moreover, important control genes can also be direclty affected by UV light. Mutation in the p53 gene is the starting point for the formation of SCC and some forms of BCC. Other BCCs originate through UV light mediated mutations of genes of the hedgehog signaling pathway which are essential for the maintainance of cell growth and differentiation. Once the keratinocytes or melanocytes have been transformed they reexpress FasL which may allow the expanding tumor to evade the attack of immuen effector cells.
Non-Melanoma Skin Cancers:
The two major forms of skin cancer are squamous cell carcinoma (SCC) and basal cell carinoma, the most common form of skin cancer. They form the upper and lower layer of the epidermis respectively. Both are classified as “nonmelanoma” and rarely spread to other parts of the body. Whereas melanoma typically begins as a mole and can occur anywhere on the body. Squamous cell carcinoma may appear as a firm red bump, a scaly patch, or open sore, or a wart that may crust or bleed easily. Basal cell carcinoma may appear as a small white or flesh-colored bump that grows slowly and may bleed.
Cutaneous Squamous cell carcinoma (SCC):
Keratinocyte dervied carinoms such as cutaneous squamous cell carinoma (SCC) include the most common class of these malignancies. Sugical excision is the most common first line treatment for cutaneous SCC. However, SCC reoccurrence is commonAlhtough both topical cheotherapeutic and immunomodulatory agents have demonstrated potential in the local treatment of superficial SCCs, cream and gel formations fail to acheive adequate penetration into deeper SCCs. Nanoparticles formed from the block copolymer poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG) has been shwon to increase the duration, bioavailability and efficacy of locally adminsitered chemotherpay drugs which minimizes the systemic toxicity associated wtih coventional chemotherpaies. (Hu, “Nonsurgical treatment of skin cancer with local delivery of bioadhesive nanoparticles” PNAS 118, 2021).
Head and neck squamous cell carcinoma (HNSCC)/Squamous cell carcinoma of the head and Neck HNSCC): reamin a substantial burden to global health. Despite improvements in treatments, many patietns develop disease recurrence. Fewer than 505 of pateints will surive beyong five years. (British J of Cancer, 2022, 126: 1186-1195).
–Detection/Staging:
A distinct staging for p16 positive HNSCC as determiend by immunostaining, a widely used clinical biomarker for infeciton with HPV, has been introduced due to its strong prognostic value in patients with squamous cell carcinomas (SC) of the oropharynx. About 30-35 of oropharyngeal tumours are attributable to HPV and are also linked to a significantly better outcome compred to pteints diagnosed with HPV negative, i.e., p16-negative disease. Unlike other cancers, reliable biomarkers for therapy planning and to monitor treatment resonse in patients with p16 negative HNSCC do not exist. Instead, initial diagnosis, as well as monitoring of HNSCC, are based solely on clinical findings and imaging with known sensitivity and specificity caveats. (British J of Cancer, 2022, 126: 1186-1195).
The detection of circulating cel-free tumour DNA (ctDNA) as a marker of minimal residual disease following curative-intent surgery holds promise for identifying patients at an increased risk of relapse, who may benefit form adjuvant radio_chemo)therapy or facilitate close monitoring with repeat resection, if needed. (British J of Cancer, 2022, 126: 1186-1195).
–Treatment:
Standard therapy for locally advanced HNSCC involves surgical resection of the primary tumour and regional lymph node metastses, radiotehrapy with or without chemotherapy or a combination of modalities. (British J of Cancer, 2022, 126: 1186-1195).
Melanoma:
Melanoma is increasing at a rate faster than any other cancer. It is the most virulent of skin cancers and highly metastatic, almost uniformly fatal within 5 years of diagnosis. The development of melanoma begins with the malignant transformation of normal human epitheial melanocytes (NHEM) located within the basement membrane of the skin. There is a correlation between the thickness of the primary melanoma and its capacity to metastasize to the draining lymph node basin(s). Once melanoma has metastasized by either route, the overal survival for patients greatly diminishes. Wherein patients with thin primary tumors are cured by surgery, patients diagnosed with metastatic melanoma (AJCC stage IV) have an overall poor prognosis, with 6 out of every 7 skin cancer deaths due to metastatic melanoma.
Treatments:
–monoclonal antibodies
—-Anti-GP240: US2005/0214307A1 provides immunoconjugates of an antibody which recognizes GP240 antigen found on melanoma cancer cells. In one embodiment, the antibody is coupled with a toxin such as gelonin, recin A chain and abrin A chain.
—-Anti-PD-1 (Program death receptor-1: Keytruda which is developed by Merk has been approved by the FDA for treatment of melanoma.
–Nucleic Acid based approaches
—-Imlygic (talimogene laherparepvec): is indicated for the treatment of meloma recurrent after initial surgery. Imlygic is a live, attenuted herpes simplex virus type 1 carrying the human GM-CSF coding sequences. Viral replcation subsequent to injection directly into the tumor is believed to trigger cell lysis and it is believed tht the release of tumor derived antigens along with the GM_CSF may also promote an antitumor effect. (Gary Wash “Biopharmaceutical benchmarks 2018” Nature Biotechnology, 36(12), 2018)
Lymphomas
Cutaneous T cell Lymphoma: