sirolimus and Carcinoma--Basal-Cell

Organ transplant recipients are prone to the development of non-melanoma skin cancer. Organ transplant recipients often develop multiple non-melanoma skin cancers and the tumors show an aggressive growth pattern, therefore surgical therapy can be difficult. Switch of the immunosuppressive regimen to mTOR-inhibitors such as everolimus or sirolimus can have an antitumor effect.. In a monocentric retrospective study we evaluated organ transplant recipients who presented with non-melanoma skin cancer in the years 2008-2010. Experience with patients who were switched to an mTOR-inhibitor due to non-melanoma skin cancer are reported in detail, and recent clinical studies are reviewed.. 60 organ transplant recipients with non-melanoma skin cancer were evaluated. Due to the development of multiple non-melanoma skin cancer within a few years, the immunosuppressive regimen was switched to everolimus in 7 patients and to sirolimus in 5 patients. Eight patients were evaluable for the effect of mTOR-inhibitors on the development of non-melanoma skin cancer; 4 patients had to discontinue the medication with mTOR-inhibitors early due to various side effects. In the year before the switch to mTOR-inhibitors, 8 patients developed 16 squamous cell carcinomas, 3 Basal cell carcinomas and 22 cases of Bowen's disease. All tumors were histologically confirmed. In the year after switch of immunosuppression, the rate of squamous cell carcinomas (n = 2) and Bowen's disease (n = 3), but not of basal cell carcinomas (n = 2) was significantly reduced. Moreover, 5 prospective randomized trials recently have demonstrated a reduced number of non-melanoma skin cancers in organ transplant recipients after switch of the immunosuppressive regimen to mTOR-inhibitors.. Switch of the immunosuppressive regimen to mTOR-inhibitors should be considered for organ transplant recipients suffering from multiple non-melanoma skin cancers.

Topics: Aged; Bowen's Disease; Carcinoma, Basal Cell; Drug Substitution; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Postoperative Complications; Randomized Controlled Trials as Topic; Retrospective Studies; Sirolimus; Skin Neoplasms

Over the past two decades, advances in the fields of cancer genetics and molecular biology have elucidated molecular pathways that cause numerous cutaneous malignancies. This in turn has spurred the rational design of molecularly targeted therapies. In this review, we discuss the molecular pathways critical to the development of nonmelanoma skin cancers and the novel pharmacologic agents that target them. Included is a review of vismodegib for basal cell carcinoma, cetuximab for squamous cell carcinomas, imatinib for dermatofibrosarcoma protuberans, and sirolimus for Kaposi's sarcoma.

Topics: Anilides; Antibiotics, Antineoplastic; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cetuximab; Dermatofibrosarcoma; Humans; Imatinib Mesylate; Piperazines; Pyridines; Pyrimidines; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms

Whether sirolimus is useful in the prevention of non-melanoma skin cancer (NMSC) remains unclear and we therefore performed this meta-analysis of randomized controlled trials to test the hypothesis that Sirolimus-based immunosuppression is associated with a decrease in NMSC.. The main outcomes were NMSC, squamous-cell carcinoma and basal-cell carcinoma. The pooled risk ratio (RR) with its 95% confidence interval (95%CI) were used to assess the effects.. 5 randomized trials involving a total of 1499 patients receiving kidney transplantation were included. Patients undergoing Sirolimus-based immunosuppression had much lower risk of NMSC (RR = 0.49, 95%CI 0.32-0.76, P = 0.001). Subgroup analyses by tumor type showed that Sirolimus-based immunosuppression significantly decreased risk of both squamous-cell carcinoma (RR = 0.58, 95%CI 0.43-0.78, P < 0.001) and basal-cell carcinoma (RR = 0.56, 95%CI 0.37-0.85, P = 0.006). The quality of evidence was high for NMSC, and moderate for squamous-cell carcinoma and basal-cell carcinoma. No evidence of publication bias was observed.. High quality evidence suggests that Sirolimus-based immunosuppression decreases risk of non-melanoma skin cancer, and Sirolimus has an antitumoral effect among kidney-transplant recipients.

Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Skin Neoplasms

Skin cancer is the most frequent malignancy in organ transplant recipients, 95% of which are nonmelanoma skin cancer, especially squamous cell and basal cell carcinomas. This paper also discusses the incidence of other tumors (eg, melanoma, Merkel cell carcinoma, and Kaposi sarcoma) that are also increased in organ transplant patients compared to the general population. Part I of this two-part series describes the latest data concerning the epidemiologic and pathogenic aspects of nonmelanoma skin cancer development in solid organ transplant recipients. This review also highlights the concept of "field cancerization," represented by extensive areas of actinic damage and epidermal dysplasia, which accounts for increased risk of aggressive skin cancer development in susceptible patients.

Topics: Carcinoma, Basal Cell; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Education, Medical, Continuing; Female; Humans; Immunocompromised Host; Incidence; Male; Melanoma; Organ Transplantation; Prognosis; Pyrimidines; Risk Assessment; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Survival Analysis; Treatment Outcome; Triazoles; Voriconazole

Immunosuppressive agents are essential for graft survival in solid-organ transplant recipients (SOTRs), but they have substantial durable side effects, including a higher incidence of aggressive nonmelanoma skin cancers (NMSCs). Hitherto, only one class of immunosuppressants, mammalian target of rapamycin inhibitors (mTORi), may inhibit skin tumor formation, however their durable effectiveness is controversial. To evaluate the sustained effectiveness of mTORi in reducing NMSCs' incidence in SOTRs, a retrospective study was conducted in a specialized dermatology clinic for SOTRs of a tertiary university-affiliated medical center. SOTRs with a history of at least one histologically proven NMSC were followed for 6 years: 3 years after transplantation, before initiation of mTORi, and 3 years under mTORi treatment. The cohort consisted of 44 SOTRs. Treatment with mTORi was initiated on average 6.27 (3.34-6.34) years following transplantation. In the 3 years before mTORi treatment initiation, the mean number of new NMSCs per patient was 2.11 (1-14). This value decreased to 1.2 (0-19) in the 3 years under mTORi treatment (p = 0.0007). Analysis by NMSC type yielded a significant decrease in both SCCs and BCCs. This study found that mTORi are effective for prolonged secondary prevention of NMSCs in SOTRs.

Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Immunosuppressive Agents; MTOR Inhibitors; Organ Transplantation; Retrospective Studies; Secondary Prevention; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

Advanced basal cell carcinomas (BCCs) are driven by the Hedgehog (HH) pathway and often possess inherent resistance to SMO inhibitors. Identifying and targeting pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify an MTOR expression signature in BCC. Pharmacological inhibition of MTOR activity in BCC cells significantly reduces cell proliferation without affecting HH signalling. Similarly, treatment of the Ptch1 

Topics: Animals; Antineoplastic Agents; Carcinoma, Basal Cell; Cell Line, Tumor; Cell Proliferation; Everolimus; Hedgehog Proteins; Humans; Imidazoles; Immunohistochemistry; Mice; Patched-1 Receptor; Protein Kinase C; Sequence Analysis, RNA; Signal Transduction; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Triazines; Zinc Finger Protein GLI1

This study aims to investigate how immunosuppression influences the protein expression of antiapoptotic members of the Bcl-2 family-namely, Bcl-xL and Mcl-1-in nonmelanoma skin cancer (NMSC) and the peritumoral epidermis of renal transplant recipients.. NMSC and peritumoral epidermis protein expression of Bcl-xL and Mcl-1 were assessed by immunohistochemistry in renal transplant recipients receiving tacrolimus or sirolimus and the general population not receiving immunosuppression.. NMSC from renal transplant recipients compared with patients not receiving immunosuppressant medications had a reduced Bcl-xL expression intensity (P = .042). Mcl-1 expression intensity in NMSC was decreased in tacrolimus-treated patients compared with sirolimus-treated patients and the nonimmunosuppressed population (P = .024). Bcl-xL expression intensity was increased in peritumoral epidermis compared with NMSC (P = .002).. It was shown for the first time that Bcl-xL and Mcl-1 expression are widespread in the peritumoral epidermis and NMSC of renal transplant recipients. Importantly in NMSC, Bcl-xL expression was reduced with immunosuppression exposure, and Mcl-1 expression was reduced in tacrolimus-treated compared with sirolimus-treated patients.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; bcl-X Protein; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mitosis; Myeloid Cell Leukemia Sequence 1 Protein; Sirolimus; Skin Neoplasms; Tacrolimus; Transplant Recipients

Mammalian Target of Rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, have been shown to reduce cutaneous carcinogenesis in organ-transplant recipients requiring for immunosuppressive treatment to prevent from allograft rejection. Clinical observations suggest that cutaneous squamous cell carcinomas (SCC) are more sensitive than basal cell carcinomas (BCC) to the antitumoral effect of these inhibitors.. To investigate if the different response of SCC and BCC to mTOR inhibitors can be explained by differential expression of molecules involved in the mTOR signaling pathway.. The expression of phospho-mTOR was immunohistocemically studied in specimens of cutaneous SCC and BCC. Results. All 15 SCCs expressed significant cytoplasmic phospho-mTOR immunoreactivity; by contrast, 12/13 BCC were completely negative, only one BCC exhibited weak phospho-mTOR immunoreactivity.. The considerably higher expression of phospho-mTOR in SCC compared to BCC is a likely explanation for their higher sensitivity to mTOR inhibitors.

Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Everolimus; Humans; Immunosuppressive Agents; Organ Transplantation; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Breast Neoplasms; Carcinoma, Basal Cell; Cell Line, Tumor; Cell Proliferation; Cisplatin; DNA-Binding Proteins; Drug Synergism; Humans; NF-kappa B; Nuclear Proteins; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases; Tumor Protein p73; Tumor Suppressor Proteins

Topics: Adult; Aged; Calcineurin Inhibitors; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Skin Neoplasms

Renal transplant recipients (RTR) have a 50-200-fold higher risk for nonmelanoma-skin cancer (NMSC) causing high rates of morbidity and sometimes mortality. Cohort-studies gave evidence that a sirolimus-based immunosuppression may inhibit skin tumor growth. This single-center, prospective, assessor-blinded, randomized trial investigated if switching to sirolimus treatment inhibits the progression of premalignancies and moreover how many new NMSC occur compared to continuation of the original immunosuppressive therapy. Forty-four RTR (mean age 59.9 years, mean duration of immunosuppression 229.5 months) with skin lesions were randomized to sirolimus or continuation of their original immunosuppression. Blinded dermatological assessment at month 6 and 12 by the same dermatologist evaluated the clinical change compared to baseline. Biopsy was performed in suspected malignancy. Already the 6-month-assessment showed significant superiority of sirolimus-therapy: a stop of progression, even regression of preexisting premalignancies (p < 0.0005). This effect was increased at month 12 (p < 0.0001). Nine patients developed histologically confirmed NMSC: one in the sirolimus group, eight in the control group, p = 0.0176. Sirolimus-based immunosuppression in RTR, even when established many years after transplantation, can delay the development of premalignancies, induce regression of preexisting lesions and decelerate the incidence of new NMSC.

Topics: Aged; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Immune Tolerance; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Precancerous Conditions; Prospective Studies; Sirolimus; Skin Neoplasms

Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Longitudinal Studies; Sirolimus; Skin Neoplasms