Venkata Yenugonda - Academia.edu (original) (raw)

Papers by Venkata Yenugonda

Cancer Research, 2020

The absence of hormone and Her2 receptor expression in triple negative breast cancer (TNBC) precl... more 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...

Neuro-Oncology, 2021

Afatinib is a small molecule, selective and irreversible ErbB family blocker. In preclinical mode... more Afatinib is a small molecule, selective and irreversible ErbB family blocker. In preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting in tumor growth inhibition and is approved for the treatment of EGFR-mutated metastatic non-small cell lung carcinoma and metastatic squamous cell lung carcinoma. Pulse dosing afatinib could potentially increase CNS exposure to reach therapeutic levels while allowing a recovery period to mitigate toxicities. We are reporting the results of a Phase I open-label, single-center, ‘3 + 3’ dose escalation study to determine the safety and tolerability of pulsatile Afatinib in patients with brain cancer and to define a recommended phase 2 dose. The study assessed the exposure of Afatinib in cerebrospinal fluid and serum, objective tumor response according to RANO criteria, progression-free survival, and overall survival, and will explore the association between molecular phenotypes and patient response. In total, 26 patien...

Molecular Cancer Research, 2021

In medulloblastoma, p53 expression has been associated with chemoresistance and radiation resista... more In medulloblastoma, p53 expression has been associated with chemoresistance and radiation resistance and with poor long-term outcomes in the p53-mutated sonic hedgehog, MYC-p53, and p53-positive medulloblastoma subgroups. We previously established a direct role for p53 in supporting drug resistance in medulloblastoma cells with high basal protein expression levels (D556 and DAOY). We now show that p53 genetic suppression in medulloblastoma cells with low basal p53 protein expression levels (D283 and UW228) significantly reduced drug responsiveness, suggesting opposing roles for low p53 protein expression levels. Mechanistically, the enhanced cell death by p53 knockdown in high-p53 cells was associated with an induction of mTOR/PI3K signaling. Both mTOR inhibition and p110α/PIK3CA induction confirmed these findings, which abrogated or accentuated the enhanced chemosensitivity response in D556 cells respectively while converse was seen in D283 cells. Co-treatment with G-actin–sequeste...

Neuro-Oncology, 2020

Glioblastoma (GBM) is considered one of the most lethal forms of human cancers, and despite consi... more 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 a...

ACS Chemical Neuroscience, 2020

Cyclin-dependent kinase 5 (Cdk5) is a prolinedirected serine (ser)/threonine (Thr) kinase that ha... more Cyclin-dependent kinase 5 (Cdk5) is a prolinedirected serine (ser)/threonine (Thr) kinase that has been demonstrated to be one of the most functionally diverse kinases within neurons. Cdk5 is regulated via binding with its neuronspecific 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.

BioTechniques, 2020

CRISPR–Cas9 has proven to be a versatile tool for the discovery of essential genetic elements inv... more CRISPR–Cas9 has proven to be a versatile tool for the discovery of essential genetic elements involved in various disease states. CRISPR-assisted dense mutagenesis focused on therapeutically challenging protein complexes allows us to systematically perturb protein-coding sequences in situ and correlate them with functional readouts. Such perturbations can mimic targeting by therapeutics and serve as a foundation for the discovery of highly specific modulators. However, translation of such genomics data has been challenging due to the missing link for proteomics under the physiological state of the cell. We present a method based on cellular thermal shift assays to easily interrogate proteomic shifts generated by CRISPR-assisted dense mutagenesis, as well as a case focused on NuRD epigenetic complex.

Journal of Clinical Oncology, 2017

e14004 Background: Pritumumab is a natural human IgG1 kappa antibody originally isolated from a r... more e14004 Background: Pritumumab is a natural human IgG1 kappa antibody originally isolated from a regional draining lymph node of a patient with cervical carcinoma. This antibody binds ectodomain vimentin on the surface of tumor cells and has demonstrated some benefit to glioblastoma patients in limited clinical trials. We wanted to determine if pritumumab inhibits glioma growth in vivo and if binding to glioma cells induces cell-mediated immunity. Methods: Pritumumab was used in flow cytometry experiments with several glioma cell lines and patient-derived neurosphere lines. Antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay was used with glioma target cells. Xenograft studies were performed in mice with and without intact B- and NK- cells. Results: We performed flow cytometry using pritumumab antibody and demonstrate binding of pritumumab to the surface of glioma cells and patient-derived glioma initiating cells. We observed significant induction of ADCC by pritumuma...

International Journal of Nanomedicine, 2019

Lipid-polymer hybrid nanoparticles (LPHNPs) are next-generation core-shell nanostructures, concep... more 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.

Cancer Research, 2018

Monoclonal antibodies (mAbs) as therapeutics for cancer have shown some success in the clinic. Th... more Monoclonal antibodies (mAbs) as therapeutics for cancer have shown some success in the clinic. These biologics are useful if targeting a cancer specific epitope. Cancer patients can generate tumor-specific B lymphocytes which can be isolated to develop human mAbs against tumor-associated antigens. The best source of anti-tumor antibodies is from sentinel lymph nodes. Pritumumab (also referred to as CLNH-11, CLN-IgG, or ACA-11) is a classic example of a natural human anti-cancer antibody. It is a natural human IgG1 kappa antibody developed by the human hybridoma technology, using B lymphocytes isolated from a regional draining lymph node of a patient with cervical carcinoma. In the original patient from whom the B lymphocyte was isolated, the bioavailability of the target antigen induced a natural immune response resulting in the generation of the pritumumab IgG. The target antigen recognized by pritumumab is cell surface expressed vimentin, also referred to as ecto-domain vimentin (...

European Journal of Pharmacology, 2018

Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a selective α4β2 n... more Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a selective α4β2 nicotinic receptor desensitizing agent and partial agonist. Sazetidine-A has been shown in our previous studies to significantly reduce nicotine and alcohol self-administration in rats. The question arises whether sazetidine-A would reduce self-administration of other addictive drugs as well. Nicotinic receptors on the dopaminergic neurons in the ventral tegmental area play an important role in controlling the activity of these neurons and release of dopamine in the nucleus accumbens, which is critical mechanism for reinforcing value of drugs of abuse. Previously, we showed that the nonspecific nicotinic antagonist mecamylamine significantly reduces cocaine selfadministration in rats. In this study, we acutely administered systemically sazetidine-A and two other selective α4β2 nicotinic receptor-desensitizing agents, VMY-2-95 and YL-2-203, to young adult female Sprague-Dawley rats and determined their effects on IV self-administration of cocaine and methamphetamine. Cocaine self-administration was significantly reduced by 0.3 mg/kg of sazetidine-A. In another set of rats, sazetidine-A (3 mg/kg) significantly reduced methamphetamine self-administration. VMY-2-95 significantly reduced both cocaine and

Human antibodies, Jan 5, 2018

Immunotherapy is now at the forefront of cancer therapeutic development. Gliomas are a particular... more Immunotherapy is now at the forefront of cancer therapeutic development. Gliomas are a particularly aggressive form of brain cancer for which immunotherapy may hold promise. Pritumumab (also known in the literature as CLNH11, CLN-IgG, and ACA-11) was the first monoclonal antibody tested in cancer patients. Pritumumab is a natural human monoclonal antibody developed from a B lymphocyte isolated from a regional draining lymph node of a patient with cervical carcinoma. The antibody binds ecto-domain vimentin on the surface of cancer cells. Pritumumab was originally tested in clinical trials with brain cancer patients in Japan where it demonstrated therapeutic benefit. It was reported to be a safe and effective therapy for brain cancer patients at doses 5-10 fold less than currently approved antibodies. Phase I dose escalation clinical trials are now being planned with pritumumab for the near future. Here we review data on the development and characterization of pritumumab, and review c...

Journal of translational medicine, Oct 18, 2017

The mitochondrial protein p32 is a validated therapeutic target of cancer overexpressed in glioma... more The mitochondrial protein p32 is a validated therapeutic target of cancer overexpressed in glioma. Therapeutic targeting of p32 with monoclonal antibody or p32-binding LyP-1 tumor-homing peptide can limit tumor growth. However, these agents do not specifically target mitochondrial-localized p32 and would not readily cross the blood-brain barrier to target p32-overexpressing gliomas. Identifying small molecule inhibitors of p32 overexpressed in cancer is a more rational therapeutic strategy. Thus, in this study we employed a pharmacophore modeling strategy to identify small molecules that could bind and inhibit mitochondrial p32. A pharmacophore model of C1q and LyP-1 peptide association with p32 was used to screen a virtual compound library. A primary screening assay for inhibitors of p32 was developed to identify compounds that could rescue p32-dependent glutamine-addicted glioma cells from glutamine withdrawal. Inhibitors from this screen were analyzed for direct binding to p32 by...

Future medicinal chemistry, 2018

better understanding of target sites and mutations has enabled the segregation of specific sites ... more better understanding of target sites and mutations has enabled the segregation of specific sites of drug activity improving drug specificity to specific disease states "

Human antibodies, Jan 7, 2018

Antibody drug conjugates (ADC's) represent a promising and an efficient strategy for targeted... more 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.

Immunotherapy, Jun 1, 2017

The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immu... more The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immunotherapies. In particular, the possibility of ex vivo expanding autologous lymphocytes that specifically recognize tumor cells has attracted much research and clinical trial interest. In this review, we discuss the historical background of tumor immunotherapy using cell-based approaches, and provide some rationale for overcoming current barriers to success of autologous immunotherapy. An overview of adoptive transfer of lymphocytes, tumor infiltrating lymphocytes and dendritic cell therapies is provided. We conclude with discussing the possibility of gene-manipulating immune cells in order to augment therapeutic activity, including silencing of the immune-suppressive zinc finger orphan nuclear receptor, NR2F6, as an attractive means of overcoming tumor-associated immune suppression.

Psychopharmacology, Jan 29, 2017

Desensitization of neuronal nicotinic acetylcholine receptors holds promise as an effective treat... more Desensitization of neuronal nicotinic acetylcholine receptors holds promise as an effective treatment of tobacco addiction. Previously, we found that sazetidine-A (Saz-A), which selectively desensitizes α4β2 nicotinic receptors, significantly decreased intravenous (IV) nicotine self-administration (SA) in rats with an effective dose of 3 mg/kg in acute and repeated injection studies. We also found that chronic infusions of Saz-A at doses of 2 and 6 mg/kg/day significantly reduced nicotine SA in rats. In continuing studies, we have characterized other Saz-A analogs, YL-2-203 and VMY-2-95, to determine their efficacies in reducing nicotine SA in rats. Young adult female Sprague-Dawley rats were fitted with IV catheters and were trained for nicotine SA (0.03 mg/kg/infusion) on a fixed ratio 1 schedule for ten sessions. The same rats were also implanted subcutaneously with osmotic minipumps to continually deliver 2 or 6 mg/kg body weight YL-2-203, VMY-2-95, or saline for four consecutiv...

Aging, 2015

Medulloblastoma (MB), a primitive neuroectodermal tumor, is the most common malignant childhood b... more Medulloblastoma (MB), a primitive neuroectodermal tumor, is the most common malignant childhood brain tumor and remains incurable in about a third of patients. Currently, survivors carry a significant burden of late treatment effects. The p53 tumor suppressor protein plays a crucial role in influencing cell survival in response to cellular stress and while the p53 pathway is considered a key determinant of anti-tumor responses in many tumors, its role in cell survival in MB is much less well defined. Herein, we report that the experimental drug VMY-1-103 acts through induction of a partial DNA damage-like response as well induction of non-survival autophagy. Surprisingly, the genetic or chemical silencing of p53 significantly enhanced the cytotoxic effects of both VMY and the DNA damaging drug, doxorubicin. The inhibition of p53 in the presence of VMY revealed increased late stage apoptosis, increased DNA fragmentation and increased expression of genes involved in apoptosis, includi...

Biochemical Pharmacology, 2015