Transcriptomic and proteomic analysis of tumor suppressive effects of GZ17-6.02 against mycosis fungoides.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL). Despite having a wide variety of therapeutic agents available for the treatment of MF, patients often suffer from a significant decrease in quality of life and rarely achieve long-term remission or complete cure, highlighting a need to develop novel therapeutic agents for this disease. The present study was undertaken to evaluate the efficacy of a novel anti-tumor agent, GZ17-6.02, which is composed of curcumin, harmine, and isovanillin, against MF in vitro and in murine models. Treatment of HH and MyLa cells with GZ17-6.02 inhibited the growth of both cell lines with IC50 ± standard errors for growth inhibition of 14.37 ± 1.19 µg/mL and 14.56 ± 1.35 µg/mL, respectively, and increased the percentage of cells in late apoptosis (p = .0304 for HH; p = .0301 for MyLa). Transcriptomic and proteomic analyses revealed that GZ17-6.02 suppressed several pathways, including tumor necrosis factor (TNF)-ɑ signaling via nuclear factor (NF)-kB, mammalian target of rapamycin complex (mTORC)1, and Pi3K/Akt/mTOR signaling. In a subcutaneous tumor model, GZ17-6.02 decreased tumor volume (p = .002) and weight (p = .009) compared to control conditions. Proteomic analysis of tumor samples showed that GZ17-6.02 suppressed the expression of several proteins that may promote CTCL growth, including mitogen-activated protein kinase (MAPK)1, MAPK3, Growth factor receptor bound protein (GRB)2, and Mediator of RAP80 interactions and targeting subunit of 40 kDa (MERIT)40.

Topical GZ21T Inhibits the Growth of Actinic Keratoses in a UVB-Induced Model of Skin Carcinogenesis.

Actinic keratoses (AKs) are premalignant intraepidermal neoplasms that occur as a result of cumulative sun damage. AKs commonly relapse, and up to 16% undergo malignant transformation into cutaneous squamous cell carcinoma. There is a need for novel therapies that reduce the quantity and surface area of AKs as well as prevent malignant transformation to cutaneous squamous cell carcinomas. We recently showed that GZ17-6.02, an anticancer agent composed of curcumin, haramine, and isovanillin, inhibited the growth of H297.T cells. This study evaluated the efficacy of a topical formulation of GZ17-6.02, known as GZ21T, in a murine model of AK generated by exposing SKH1 mice to UVR. Treatment of mice with topical GZ21T inhibited the growth of AKs by decreasing both lesion count (P = 0.012) and surface area occupied by tumor (P = 0.002). GZ21T also suppressed the progression of AKs to cutaneous squamous cell carcinoma by decreasing the count (P = 0.047) and surface area (P = 0.049) of lesions more likely to represent cutaneous squamous cell carcinoma. RNA sequencing and proteomic analyses revealed that GZ21T suppressed several pathways, including MAPK (P = 0.025), phosphoinositide 3-kinase-protein kinase B (P = 0.04), HIF-1α (P = 0.016), Wnt (P = 0.025), insulin (P = 0.018), and ERBB (P = 0.016) signaling. GZ21T also upregulated the autophagy-promoting protein AMPK while suppressing proteins such as PD-L1, glutaminase, pAkt1 S473, and eEF2K.

Construction of a Secondary Enclosure for UVB Irradiation of Mice.

UV irradiation is commonly used in murine models of skin cancers. Despite the popularity of using UVB rays to model photocarcinogenesis in animals, there is a lack of standardization in the secondary enclosures used to administer radiation. An appraisal of the literature also shows a general lack of details regarding the materials and procedures utilized in the fabrication of such enclosures. We present in this study a detailed overview of the construction of a UVB exposure chamber that successfully induces lesions in hairless mice. A standardized protocol for producing a UVB enclosure may reduce methodological variation in future studies seeking to investigate photocarcinogenesis in animals.

GZ17-6.02 Inhibits the Growth of EGFRvIII+ Glioblastoma.

Epidermal Growth Factor Receptor (EGFR) is amplified in over 50% of glioblastomas and promotes tumor formation and progression. However, attempts to treat glioblastoma with EGFR tyrosine kinase inhibitors have been unsuccessful thus far. The current standard of care is especially poor in patients with a constitutively active form of EGFR, EGFRvIII, which is associated with shorter survival time. This study examined the effect of GZ17-6.02, a novel anti-cancer agent undergoing phase 1 studies, on two EGFRvIII+ glioblastoma stem cells: D10-0171 and D317. In vitro analyses showed that GZ17-6.02 inhibited the growth of both D10-0171 and D317 cells with IC50 values of 24.84 and 28.28 µg/mL respectively. RNA sequencing and reverse phase protein array analyses revealed that GZ17-6.02 downregulates pathways primarily related to steroid synthesis and cell cycle progression. Interestingly, G17-6.02's mechanism of action involves the downregulation of the recently identified glioblastoma super-enhancer genes WSCD1, EVOL2, and KLHDC8A. Finally, a subcutaneous xenograft model showed that GZ17-6.02 inhibits glioblastoma growth in vivo. We conclude that GZ17-6.02 is a promising combination drug effective at inhibiting the growth of a subset of glioblastomas and our data warrants further preclinical studies utilizing xenograft models to identify patients that may respond to this drug.

Mouse models for actinic keratoses.

Actinic keratoses (AKs) represent a premalignant skin condition due to chronic sun damage that dramatically increases in prevalence in the aging population. Currently, animal models of AKs utilize photocarcinogenesis, chemical carcinogens, or targeted gene modulation, and each method possesses unique strengths and weaknesses. Models using photodamage most comprehensively describe methods for preferentially selecting AK lesions, while replicating the pathogenesis of AKs with greater fidelity than models utilizing other carcinogenic methods. The following review of current murine models of AKs will aid in the selection of mouse models appropriate for future in vivo studies to test the efficacy of novel therapeutic agents for the treatment of AKs.

Rare presentation of inflammatory myofibroblastic tumor on a digit.

Inflammatory myofibroblastic tumors (IMTs) are rare soft tissue neoplasms consisting of a mixture of spindle-shaped myofibroblasts or fibroblasts and a variable inflammatory infiltrate composed of eosinophils, plasma cells, and lymphocytes. Associations with trauma and infectious agents have been proposed, but the etiology is unknown. While IMT predominantly develops in the lungs of pediatric patients or young adults, extrapulmonary IMT is well documented and may occur anywhere. Cutaneous IMT is rare and few have been reported on the hand in the English language. The mean age of onset is 10 years, with a slight female predilection. IMT demonstrates intermediate malignant potential, with a tendency to recur locally. Metastases are rare. According to a recent review, anaplastic lymphoma kinase (ALK) positivity on immunohistochemistry is related to local recurrence, but not distant metastases. We report an unusual case of a 36-year-old male, with a lesion on the right second digit, displaying classic histopathologic and immunohistochemical features of IMT, including ALK staining, and confirmatory fluorescence in situ hybridization-proven ALK gene rearrangement.

Phototherapy trends in dermatology.

BACKGROUND: Use of phototherapy in the United States declined during the 1990s, largely due to unfavorable economic incentives. The trends in phototherapy since then are not well characterized. METHODS: We analyzed the National Ambulatory Medical Care Survey (NAMCS) data on quantity of phototherapy visits and associated diagnoses and payment sources. Trends were assessed by linear regression. RESULTS: There were an estimated 230 000 outpatient phototherapy visits per year, with an increasing trend over time (p = 0.03). Dermatologists managed 87% of the visits. Leading diagnoses associated with phototherapy included psoriasis (25%), dermatitis NOS (6%), vitiligo (6%), other dyschromia (6%), and actinic keratosis (5%). CONCLUSIONS: Use of phototherapy for psoriasis has remained relatively low up to 2010. However, phototherapy may be becoming more frequent for conditions other than psoriasis.

Patterns of disease and treatment of cold sores.

BACKGROUND: Cold sores are a common condition that can cause significant morbidity and mortality. Antivirals are the typical treatment for cold sores, but the ways in which these medications are used to treat cold sores are not well studied. PURPOSE: To determine the main treatments prescribed for cold sores and trends in their management over time. METHODS: A retrospective analysis of the National Ambulatory Medical Care Survey database was used to analyze outpatient visits for cold sores from 1993 to 2009. Patients were included in the data analysis if they had one of the following three diagnoses reported for their reason-for-visit codes: cold sores (CS), herpes simplex (HS) or herpes simplex with cold sores (HS/CS). RESULTS: There was a decreasing trend in the number of annual patient visits for cold sores. The majority of patients were mainly young to middle adulthood, white women. The top two most commonly prescribed medications were acyclovir followed by valacyclovir. Valacyclovir use increased in all three populations, while acyclovir use decreased. CONCLUSIONS: The trends observed may indicate that physicians are evolving their treatment strategies to implement newer antiviral medications. This may prove more efficacious for the treatment of cold sores.

Incidence, risk factors, and preventative management of skin cancers in organ transplant recipients: a review of single- and multicenter retrospective studies from 2006 to 2010.

BACKGROUND: Organ transplant recipients (OTRs) taking immunosuppressants are at high risk of skin cancer, which is the most common malignant condition in OTRs, so dermatologic surveillance is important for OTRs. OBJECTIVES: To characterize the most common skin cancers arising from chronic immunosuppression in OTRs. METHODS: A PubMed search for retrospective single- and multicenter studies reporting skin cancer incidence from 2006 to 2010 was undertaken. Data regarding each study's immunosuppressive regimen, affected skin cancer cohort, and associated risk factors were extracted. RESULTS: Thirty-six articles that met our inclusion criteria reported incidences of nonmelanoma skin cancer (NMSC), Kaposi's sarcoma, melanoma, and Merkel cell carcinoma. NMSC was the most commonly reported cancer of all skin cancers after transplantation. Common risk factors were sex, age, sunlight exposure, and immunosuppressive agent-related (duration, type). CONCLUSION: Sun education programs and frequent screenings in organ transplant clinics have provided the best preventative strategies after transplantation, although the characteristics of the immunosuppressive regimen also play an important role. Thus, the adjuvant strategy of modifying immunosuppression may be effective when confronting severe transplant-associated skin cancer. Although the decision-making process for curbing levels of immunosuppression is difficult, further long-term, randomized controlled studies should assess the effect of using less immunosuppressant medication while preserving graft function.

Therapeutic modalities for localized psoriasis: 308-nm UVB excimer laser versus nontargeted phototherapy.

UVB phototherapy is an effective treatment modality for psoriasis. For patients with localized plaque-type lesions, 308-nm excimer laser phototherapy offers rapidly delivered, targeted, high UVB doses, while sparing adjacent healthy skin. We aimed to compare the advantages and disadvantages of the 308-nm xenon chloride (XeCI) UVB excimer laser with nontargeted broadband UVB (BB-UVB), narrowband UVB (NB-UVB), and psoralen plus UVA (PUVA) phototherapies. A PubMed search for studies evaluating the efficacy and safety of the laser versus nontargeted phototherapeutic modalities was conducted. Three prospective nonrandomized studies compared NB-UVB with excimer laser phototherapy. No head-to-head studies were found for BB-UVB or PUVA compared to excimer laser. Both the 308-nm excimer laser and nontargeted phototherapies were found to effectively clear localized psoriasis. Although it is proposed that excimer laser exclusively treats diseased skin with better response rates, split-body trials revealed no differences. Long-term studies are necessary to compare the effects of high-dose excimer laser regimens with nontargeted phototherapies.

Comparative efficacy of biologics in psoriasis: a review.

BACKGROUND: Psoriasis is a chronic, immune-mediated skin disease that also has systemic manifestations. Safe and effective long-term treatments are needed. Biologic treatments that inhibit the immunopathogenesis of psoriasis have helped meet this need. PURPOSE: The purpose of this study was to compare the efficacy of biologic therapies used for psoriasis. METHODS: A literature search was performed using PubMed and the keywords '(PASI-75 OR efficacy) AND psoriasis AND (adalimumab OR alefacept OR etanercept OR infliximab OR ustekinumab).' Randomized, double-blind, and placebo-controlled studies on US FDA-approved biologics were selected. Studies assessing the proportion of subjects achieving 75% improvement in Psoriasis Area and Severity Index (PASI-75) within a 12-week period were included. Studies on pediatric populations and psoriatic arthritis were excluded. The weighted average of PASI-75 for each reported regimen was calculated to determine the efficacy of biologic agents used for moderate-to-severe psoriasis. Tolerance and secondary efficacy measures were also examined for the selected studies. RESULTS: FDA-approved regimens of adalimumab, infliximab, ustekinumab, and alefacept were effective in treating moderate-to-severe psoriasis. Weighted average PASI-75 scores for infliximab, ustekinumab, adalimumab, etanercept, and alefacept were 78.6%, 72.1%, 70.5%, 48.1%, and 21%, respectively. LIMITATIONS: The comparative efficacy of biologic agents data was limited to 12 weeks, thus generalizing the results to longer treatment periods may not be accurate. CONCLUSIONS: Various biologic agents for psoriasis were effective at 12 weeks in placebo-controlled trials. Available data cannot fully account for situations in clinical practice, in which combination and longer duration of therapy may be required. When choosing the most effective or best agent, multiple factors should be considered including patient preference, cost, tolerance, adverse effects, dosing schedule, and mode of administration.