Ariana Waters’s research while affiliated with John Wayne Cancer Institute and other places

Glioblastoma (GBM) is considered one of the most lethal forms of human cancers, and despite considerable advances in multimodality treatments, it remains an incurable disease with an overall survival of 14 to 16 months after diagnosis. Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), an oral alkylating agent, remains the standard-of-care for GBM. However, intrinisic or acquired resistance to TMZ due to over expression of O6-methylguanine-DNA methyltransferase (MGMT) results in initial treatment inefficacy or tumor relapse, highlighting the significant need for improved treatment strategies. Recently, much effort has been directed towards creating novel TMZ analogs to address the clinical barriers associated with TMZ. While some reported TMZ analogs showed improved brain permeability and anticancer effects in preclinical models, none of them have progressed to testing in humans. There is therefore significant room to improve the brain permeability and anticancer effect profiles of TMZ by incorporating yet unexplored functional groups into new analogs. We have designed and synthesized a series of novel C8-substituted TMZ analogs and have evaluated their anticancer potency against a panel of GBM cell lines with variable levels of MGMT expression. Encouragingly, our analogs demonstrated promising anti-cancer effect in both MGMT low and high expressing lines. We then evaluated our analogs in a variety of cell based assays to compare their activity with TMZ, and performed in vivo brain permeability and anti-tumor efficacy assays in mouse flank models. Our results demonstrated that several of our analogs clearly display improved anti-cancer effects and increased brain permeability over TMZ. This work points to a new direction for the development of novel TMZ analogs for improved patient survival.

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine (ser)/threonine (Thr) kinase that has been demonstrated to be one of the most diversely functional kinases within neurons. Cdk5 is regulated via binding with its neuron-specific regulatory subunits, p35 or p39. Cdk5-p35 activity is critical for a variety of developmental and cellular processes in the brain, including neuron migration, memory formation, microtubule regulation and cell cycle suppression. Aberrant activation of Cdk5 via the truncated p35 byproduct, p25, is implicated in the pathogenesis of several neurodegenerative diseases. The present review highlights the importance of Cdk5 activity and function in the brain and demonstrates how deregulation of Cdk5 can contribute to the development of neurodegenerative conditions such as Alzheimer's and Parkinson's disease. Additionally, we cover past drug discovery attempts at inhibiting Cdk5-p25 activity and discuss which types of targeting strategies may prove to be the most successful moving forward.

The absence of hormone and Her2 receptor expression in triple negative breast cancer (TNBC) precludes the use of targeted therapy available for other breast cancer subtypes, and cytotoxic chemotherapy such as paclitaxel and doxorubicin remains the mainstay of treatment for TNBC. However, patients with TNBC have higher relapse rates, with residual disease after chemotherapy and shorter overall survival, leaving space for further improvement beyond these cytotoxic chemotherapies. We have identified a new chemical entity, VMY- BC-1, that potently blocks growth in TNBC cell lines compared to other breast cancer subgroups or normal-like breast epithelial cells. Our molecule reduces invasion and induces apoptosis in TNBC cell lines. VMY-BC-1 is orally bioavailable and has promising pharmacological properties, and has demonstrated TNBC growth inhibition in vivo. Quantitative proteomics with tandem mass tag (TMT) and Ingenuity Pathway Analysis (IPA) identified significantly altered pathways upon treatment with VMY-BC-1 in the human TNBC cell line, MDA-MB-231. These include activation of the apoptosis, autophagy, and DNA damage pathways, and inhibition of the mTOR1, PI3K, and AKT pathways (Z score = 0.156, p value =1.97E-10). Thermal proteome profiling (TPP) analysis identified proteins interacting with VMY-BC-1 that relate to activated autophagy and DNA damage pathways, such as UNC-51 like kinase 1 (ULK1) and ataxia-telangiectasia mutated (ATM). Importantly, in line with our observations, in addition to a significantly lower expression of ULK1 on TNBC (T-test; p value = 2.127E-10), we observed that patients with tumors with high ULK1 expression have a larger relapse-free survival (n=3,951; HR=0.77 [0.69-0.86]; log rank; p=5.1E-06). Moreover, our small molecules activated autophagy mediated signaling pathways through ULK1 phosphorylation. These data suggest that autophagy and DNA damage pathways could be therapeutically targeted in TNBC. Citation Format: Venkata Mahidhar Yenugonda, Ariana Waters, Sivaramakrishna Yadavalli, Diego Marzese, Surojeet Senugupta, Elmar Nurmammadov, Yueqin Quan, Natsuko Nomura, Annamarie Allnutt, Santosh Kesari. Small molecule targeting regulated cell death pathways in treating triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-12.

Glioblastoma (GBM) is one of the most lethal human tumors, and despite considerable advances in multimodality treatments consisting of surgical removal, radiation and chemotherapy, overall survival is 14 to 16 months after diagnosis. Therefore, there is a need to target non-apoptotic death pathways and inhibit pro-survival signaling mechanisms that contribute to both tumorigenesis and treatment resistance. Depending on tumor type and environment, autophagy modulation plays an important role in tumor cell survival and inhibition pathways. Increasing evidence supports that chemical modulation of autophagy inhibition and activation holds a therapeutic potential and these studies have led to the initiation of multiple clinical trials combining chemotherapeutic agents and autophagy inhibitors and activators for various cancer types. However, recent studies have also demonstrated a therapeutic potential for enhancers of autophagy in GBM. This clearly demonstrates the need for further investigation into the autophagy induced mechanism of GBM, and the development of better treatments. We have identified a new chemical entity VMY-BC-1 that showed promising effects in both serum and patient-derived glioma cell lines. Drug target engagement studies identified an autophagy induction protein, UNC-51 like kinase 1 (ULK1), as the main target of VMY-BC-1, in which VMY-BC-1 covalently bound to the protein’s active pocket and increased ULK1 phosphorylation.ULK1 is a component of the ULK1 complex (ULK1-ATG13-FIP200) that is essential for inducing autophagy, a lysosome-dependent mechanism of intracellular degradation for maintaining cellular homeostasis. Additionally, our molecule cross talks to the apoptotic and DNA damage pathways, which could potentially overcome treatment resistance.VMY-BC-1 is orally bioavailable, brain penetrant, and inhibits cell invasion and tumor growth in GBM flank models, making this small molecule an ideal candidate for further development. We hypothesize that activating ULK1-modulated autophagy will be a therapeutic strategy for GBM growth inhibition

Lipid–polymer hybrid nanoparticles (LPHNPs) are next-generation core–shell nanostructures, conceptually derived from both liposome and polymeric nanoparticles (NPs), where a polymer core remains enveloped by a lipid layer. Although they have garnered significant interest, they remain not yet widely exploited or ubiquitous. Recently, a fundamental transformation has occurred in the preparation of LPHNPs, characterized by a transition from a two-step to a one-step strategy, involving synchronous self-assembly of polymers and lipids. Owing to its two-in-one structure, this approach is of particular interest as a combinatorial drug delivery platform in oncology. In particular, the outer surface can be decorated in multifarious ways for active targeting of anticancer therapy, delivery of DNA or RNA materials, and use as a diagnostic imaging agent. This review will provide an update on recent key advancements in design, synthesis, and bioactivity evaluation as well as discussion of future clinical possibilities of LPHNPs.

Antibody drug conjugates (ADC's) represent a promising and an efficient strategy for targeted cancer therapy. Comprised of a monoclonal antibody, a cytotoxic drug, and a linker, ADC's offer tumor selectively, reduced toxicity, and improved stability in systemic circulation. Recent approvals of two ADC's have led to a resurgence in ADC research, with more than 60 ADC's under various stages of clinical development. The therapeutic success of future ADCs is dependent on adherence to key requirements of their design and careful selection of the target antigen on cancer cells. Here we review the main components in the design of antibody drug conjugates, improvements made, and lessons learned over two decades of research, as well as the future of third generation ADCs.