Visualizing Antineoplastic Activity with a Whole Organism Drosophila melanogaster Screen

Cancer is a disease characterized by high mitosis rates with a loss of regulation. Many antineoplastics, those drugs used to treat cancer, act by slowing or halting mitosis. We are developing a whole-organism screening protocol to identify novel antineoplastics. After exposing Drosophila melanogaster eggs and larva to a compound, their growth rate and population decrease if mitosis inhibition or arrest occur. We screened several compounds from the National Cancer Institute’s (NCI) Developmental Therapeutics Program (DTP). Our screen successfully identified two compounds, toyocamycin and stictic acid, previously identified as possible antineoplastics. Toyocamycin killed a fraction of the population proportional to the dose concentration resulting in full mortality at 100 and 200 µM. At low doses, toyocamycin also slowed larval development by a mean of one day. RNAseq showed that no genes were differentially expressed in mature flies after toyocamycin exposure was halted. Stictic acid delayed larval growth by an equal or greater margin compared to toyocamycin. These results demonstrate that decreases in Drosophila growth or population can predict a compound’s antineoplastic activity and toxicity.

Mouse Models of Glioblastoma for the Evaluation of Novel Therapeutic Strategies

Glioblastoma (GBM) is an incurable brain tumor with a median survival of approximately 15 months despite an aggressive standard of care that includes surgery, chemotherapy, and ionizing radiation. Mouse models have advanced our understanding of GBM biology and the development of novel therapeutic strategies for GBM patients. However, model selection is crucial when testing developmental therapeutics, and each mouse model of GBM has unique advantages and disadvantages that can influence the validity and translatability of experimental results. To shed light on this process, we discuss the strengths and limitations of 3 types of mouse GBM models in this review: syngeneic models, genetically engineered mouse models (GEMMs), and xenograft models, including traditional xenograft cell lines and patient-derived xenograft (PDX) models.

Synthesis and Anticancer Activity of Novel Benzofurancarboxamides

In our present work, we presented an efficient synthesis and anticancer activity evaluation of some novel benzofurancarboxamides. Our proposed approaches provide the possibility to design benzofurans diversity with a considerable chemical novelty. The synthesized substances were selected by the National Cancer Institute (NCI) Developmental Therapeutics Program for the in vitro cell line screening to investigate their anticancer activity. The compounds with significant levels of anticancer activities have been found that can be used for further optimization.

3300 Progesterone receptor alters lipid biology in luminal breast cancer

OBJECTIVES/SPECIFIC AIMS: These studies seek to evaluate hormonal regulation of luminal breast cancer lipid metabolism and to identify targetable progesterone-mediated changes in lipid biology that contribute to therapeutic resistance in breast cancer. METHODS/STUDY POPULATION: Established and patient-derived luminal breast cancer cell lines, which express ER and PR, were used for this study. RNA transcript and protein expression levels were evaluated by qRT-PCR and immunoblot, respectively. Broad scale lipidomics of progesterone-treated cells was conducted via ultra-high pressure liquid chromatography-mass spectrometry (UHPLC-MS) through the UCD Skaggs School of Pharmacy Mass Spectrometry Core. RESULTS/ANTICIPATED RESULTS: Data mining of previously published microarray data of CK5+ and CK5− syngeneic cancer sublines revealed that CK5+ cells have increased expression of lipid processing genes, including LPL and PPARG. As progestin treatment induces a subpopulation of cells to turn on CK5 expression in luminal breast cancers, UHPLC-MS-based lipidomics analysis will expose whether modulation of the lipid landscape occurs in all cells with progesterone treatment, or whether this phenomenon is heightened specifically in CK5+ cells. I also expect that ER+ breast cancers with progestin induced-altered lipid content, such as lipid droplet formation, will evade therapy-induced death. DISCUSSION/SIGNIFICANCE OF IMPACT: There are numerous approved and developmental therapeutics targeting lipid biology. By determining if progestins alter lipid metabolic genes specifically in CK5+ CSCs, which are endocrine resistant, strategies may be devised to target these resistant cells using combination therapy in conjunction with existing therapies to prevent tumor recurrence.