Melanoma. Kevetrin will be evaluated as a single agent for its ability to induce apoptosis in melanoma cell lines A375, SKMel5 (both of which have the BRAFV600E mutation), SKMel2 (which has an NRAS mutation), and SKMEL31, (which has wild type BRAF and NRAS genes). The methods by which apoptosis will be assessed are identical to those proposed above for the RCC studies. To determine the activity of Xxxxxxxx against melanoma xenografts, the drug will be studied alone and in combination with the VEGFR antagonist Axitinib. The rationale for this plan is based on our previous work with an HDM2 antagonist which demonstrated limited antitumor activity when used as a single agent but sustained tumor non-progression when used in combination with the multikinase inhibitor sorafenib. The decision to substitute Axitinib for sorafenib is based on its more potent VEGFR inhibitory activity. For these xenograft studies, 1 x 107 A375, SKMel2, and SKMEL31 melanoma cells will be implanted subcutaneously into the flanks of 40 nude/beige mice. Once tumors have reached the diameter of 7 mm, the tumor- bearing mice will be divided into 4 treatment groups and treated with Kevetrin alone, axitinib alone (30 mg/kg daily), saline (control), or both Kevetrin + axitinib. Mice are treated daily by gavage for 21 days. Tumor size is measured thrice weekly. On day #10, three mice from each treatment group will be sacrificed and their tumors excised and divided into two halves. One half will be frozen for subsequent biochemical analysis and the other half fixed in formalin for paraffin embedding. At the end of the study (Day #21 or when the control tumors reach a diameter of 20mm, whichever comes first), the remaining mice will be sacrificed and their tumors excised and processed as described above for the Day #10 tumors. Study endpoints will be the same as those proposed above in the RCC analyses. Drugs: The sunitinib used in these studies will be unused clinical grade material provided to us by patients who are no longer receiving the drug. The investigational VEGFR2 antagonist axitinib will be purchased from LC Laboratories.
Melanoma. Where primary discussion & treatment undertaken by Xxxxx surgeon, Secondary discussion at Skin MDT Skin MDT for discussion re trial eligibility and general skin examination Involvement of the Specialist SMDT may be required Where primary discussion & treatment undertaken by Xxxxx surgeon, Secondary discussion at Skin MDT Skin MDT for discussion re trial eligibility and general skin examination Unless Xxxxx’x disease elsewhere in traditionally sun-protected skin sites, discuss with member of Xxxxx MDT to exclude labia minora VIN and VAIN Skin MDT Primary discussion and treatment Refer for biopsy to exclude other pathologies (Paget’s disease, invasive neoplasia) Primary discussion & treatment Secondary discussion Skin MDT Gynae MDT As increased risk of cervical neoplasia, refer for advice on possible cervical pathology Primary discussion & treatment Secondary discussion Primary discussion Skin MDT Skin MDT Discuss with Xxxxx MDT to ensure no internal invasive cancer or Paget’s involvement of labia minora or vaginal canal Gynae MDT Secondary discussion & treatment The Urology Cancer MDT reviews and takes the lead in all invasive non melanoma skin cancer cases, involving male genitalia. Certain tumour types have additional guidelines: Guidelines as for the general xxxxx stated above for any excision. In addition, any melanoma arising in the male urethra, and dealt with by a urological surgeon with principle discussion at the Urology Cancer MDT, should also be discussed secondarily at the Skin MDT; where issues including trial eligibility and general skin examination can be reviewed.
Melanoma. This is the rarest but most dangerous form of skin cancer. It has the appearance of a new spot, freckle or mole which changes colour, thickness or shape over a period of a month and may appear anywhere on the body. Melanoma is often a fast growing cancer, which spreads quickly to other parts of the body. It can occur from adolescence onwards and is most common in people aged between thirty and fifty years old. In rare cases it may develop in children. All skin cancers are curable if treated promptly in the early stages. The key to early detection is being alert to any new or changing freckle or mole, or any sore that does not heal. It should be noted that skin cancers are rarely painful in their early stages.
