Desensitization Of Basal Cell Carcinoma To The Anti-Tumoral Effect Of Vitamin D

The relationship between Vitamin D and NMSC is not very clear. Most of human studies in literature in regards to vitamin D and NMSC are epidemiological which are inconsistent and inconclusive. Mechanistic studies about BCC are few, and mostly are animal models or cell cultures. The main goal for this study is to interpret the impact of vitamin D status on the onset and progression and possibly treatment of basal cell carcinoma. Three tissue samples were collected from BCC patients (Cancer, Proximal, and Distal), and from cancer-free individuals from southeast Michigan. This study design helps identifying alterations in the genetic profile of patient\u27s non-cancerous tissue based on their location in relation to the cancer. This idea has a great significance in understanding factors that may influence the onset and progression of the disease, as well as the risk for future recurrence. Our data indicated that Vitamin D ability to negatively regulate mTOR and Hedgehog-Gli signaling pathways was diminished. In addition, BCC cancer tissue and its feeding cells seem to up-regulate vitamin D activation enzymes, vitamin D receptor along with its co-activators proposing higher local activity of vitamin D in the cancer tissue. In conclusion, we believe that the anticipated role of vitamin D is not conserved in basal cell carcinoma cells

The Effect of a Sun Damage Simulation Photography App on the Skin-Protective Behavior Intentions of Women with Children Age 18 or Younger

Abstract Background: Skin cancer is the most common form of cancer diagnosed in the U.S. annually, despite being a largely preventable disease through the limitation of ultraviolet radiation exposure. Attempts to decrease its incidence have focused on appearance-based interventions. These have been effective at improving sun-protective behaviors among various subpopulations including people of color. Anecdotal observations suggest mothers more frequently utilize sun protection for their children than on themselves. Purpose: The purpose of this project was to gain an understanding of the sun protection practices and beliefs of Caucasian and African American mothers, to assess the response to an appearance-based intervention for motivating sun-protective behaviors, and to educate mothers about skin cancer risks and prevention. Methods: The project was comprised of multiple phases. First, a retrospective chart review was performed to assess the frequency of sun protection counseling at well-child visits for Caucasian and African American children between the ages of four and 18 years. In the intervention phase, mothers completed a survey about their attitudes towards tanning, sun protection, their current practices, and the practices they use for their children. Their actual melanoma risk was calculated using the Self-Assessment Melanoma Risk Score (SAMScore). Next, they used the Sunface App, a facial morphing smartphone application that simulates the effects of sun damage on facial photography. Then, they were provided an educational presentation consisting of the American Academy of Dermatology’s Spot Skin Cancer campaign. Results: The chart review indicated sun protection occurred at 44% of well-child visits (n = 61) with no significant differences between race, gender, or among the age of the patients. Survey results found no significant difference between racial groups with regards to sun protection beliefs, personal practices, and protection for their children (n =14). Older mothers, and those that reported high frequencies of personal sunscreen use were more likely to put sunscreen on their children (rs = .696, p \u3c .05; rs = .533, p = 0.050, respectively). Having a higher actual risk for melanoma was not associated with more perceived risk of skin cancer by mothers (F=.745, p \u3e.05). Sunface app reactions fell under three main themes: surprise or disbelief, negative feelings about their appearance, or motivation to increase sunscreen use. Discussion: While few statistically significant results were found in the study, findings indicate a need for education to mothers about their risk for skin cancer development. Future research is needed to determine factors that may influence the inclusion of sun protection counseling at well-child visits including family histories or competing demands. The Sunface application shows promise as a convenient and effective tool to motivate mothers to improve sun protection practices. Qualitative follow-up survey responses (n = 2) indicated participants were motivated to increase sun protection practices following the intervention. Study results and sample size may have been limited by the Fall/Winter timing of the project as well as the percentage of international and low-income patient population at the project setting. Conclusion: The Sunface application elicited powerful responses by participants and may motivate improved sun protection practices. Primary care providers are in prime, unique positions to counsel their patients on risks for skin cancer and its prevention. With limited visit times and competing demands, alternative methods of providing preventive counseling may need to be considered

Cancer Vaccine Final IQP

The goal of this project was to document and evaluate the technology of cancer vaccines, to determine whether they are worth the recent media hype, to document any associated problems, and to help prioritize future directions. We performed a review of the research literature and conducted interviews with academic cancer researchers. Based on the data, of the six major categories of cancer vaccines, tumor infiltrating lymphocyte (TIL) and chimeric antigen receptor (CAR) vaccines have shown the highest efficacies. In the future, we recommend using combination vaccines (especially with antibodies for immune checkpoint inhibitors), adjuvants, recall antigens, and identifying and using a patient¡¯s own specific tumor neo-antigens. We recommend that funding be continued for this research

DEVELOPMENT OF NANOLIPOSOMES FOR THE TREATMENT OF BRAF V600E MUTATED PARENT AND VEMURAFENIB-RESISTANT MELANOMA

Melanoma is one of the most aggressive and deadliest types of skin cancer. Currently, off-target toxicities and the rapid resistance development of metastatic melanoma mainly restrict the efficiency of the treatments. This thesis presents efforts towards developing liposomes to address current problems of BRAF-mutant metastatic melanoma. EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF V600E Mutated Parent and Resistant Melanoma In order to address off-target toxicities of the targeted therapy of MEK inhibitor trametinib (TMB), we developed a physically stable EphrinA1-mimicking peptide (YSA) anchored TMB-loaded PEGylated nanoliposomes (YTPLs). The YTPLs were evaluated in BRAFV600E-mutated parent cell lines (A375 and SK-MEL-28) and vemurafenib-resistant cell lines (A375R and SK-MEL-28R). A differential scanning calorimetry (DSC) study confirmed that TMB was retained in a solubilized state within the lipid bilayers. No burst release was observed of TMB in 24 h and negligible hemolysis was observed at therapeutic concentrations of TMB. YTPL showed higher intracellular uptake in parental cell lines compared to vemurafenib-resistant cell lines. Western blot analysis and a cytotoxicity study with the EphA2 inhibitor confirmed a reduction in EphA2 expression in resistant cell lines. Thus, YTPLs can be useful for metastatic melanoma-specific delivery of TMB. Development of BRD4 PROTAC and anti-fibrotic agent co-loaded PEGylated Nanoliposome for BRAF inhibitor resistant Melanoma In the present study, we proposed a new treatment strategy for the treatment of vemurafenib-resistant melanoma by targeting to both cancer cells and tumor stroma. A BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed in a synergistic cytotoxic ratio against vemurafenib-resistant melanoma. Both the molecules have extremely poor aqueous solubility. Citric acid was used to improve the loading of both the molecules in ARNIPL. ARNIPL with mean particle size 111.1 ± 6.55 nm exhibited more than 90% encapsulation efficiency (EE) for both the drugs and was found to be physically stable for a month. Both the molecules and ARNIPL showed significantly higher cytotoxicity, apoptosis and downregulation of target proteins BRD4 and c-Myc in vemurafenib-resistant cell line (A375R). Vasculogenic mimicry and clonogenic potential of A375R were significantly inhibited by ARNIPL. Tumor growth inhibition in 3D spheroid of A375R and 3D spheroid of co-culture of A375R+Dermal fibroblasts model with reduction of TGF-β1 was observed with ARNIPL treatment. Therefore, ARNIPL could be a novel therapeutic approach for the treatment of vemurafenib-resistant melanoma

ELUCIDATING THE ROLE OF THE TYROSINE PHOSPHATASE, SHP-2, IN REGULATION OF PD-L1 EXPRESSION IN NON-SMALL LUNG CANCER USING BOTH BIOCHEMICAL ANALYSES AND REAL-WORLD GENOMIC INFORMATION

Immune checkpoint inhibitors (ICIs), especially those that target programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1), have been shown to provide substantial clinical benefit in many patients with non-small cell lung cancer (NSCLC). While these therapeutic agents can be highly effective in the correct context, the biological systems that malignant cells draft from normal activities of the cell are poorly characterized. Tumor cell-specific expression of PD-L1 is likely important for clinical benefit from PD-1 and PD-L1 inhibitors. It is known that PD-L1 is inappropriately expressed in many cancers harboring mutations in the RAS family of genes. The KRAS gene is mutated in as many as 30% of NSCLC tumor and drives tumor proliferation. Because there are no FDA-approved KRAS-targeting agents available for NSCLC patients, ICI therapy has been used in patients with tumors harboring mutations in the KRAS gene with clinical success. However, utilization of these therapies will remain hindered until there is a more complete understanding of the mechanisms governing the expression of targets of ICIs, specifically of PD-L1. The work in this dissertation explores the role of the tyrosine phosphatase, SHP-2. SHP-2 has been scrutinized as an important signaling molecule in a variety of cancers that links the activity of several signaling cascades as a regulator of KRAS, resulting in the clinical development of inhibitors of SHP-2. The work encompassed in these studies takes two complementary approaches to explore the role of SHP-2 in control of PD-L1 expression. First, publicly available real-world genomic information was used to establish a connection between the activity and/or expression of SHP-2 and PD-L1 in tumors and how expression relates to response to ICI therapy. Second, this work further sought to elucidate the molecular mechanism by which SHP-2 impacts the expression of PD-L1 in an NSCLC cell line model system. From these investigations, this work established that SHP-2 and PD-L1 have an expression relationship in clinical samples that may impact response to ICI therapies and experimentally identified a possible mechanism by which SHP-2 impacts PD-L1 expression in NSCLC