Potential Applications In Oncology Research Articles

Chinese Oncologists' Perspectives on Integrating AI into Clinical Practice: Cross-Sectional Survey Study.

The rapid development of artificial intelligence (AI) has brought significant interest to its potential applications in oncology. Although AI-powered tools are already being implemented in some Chinese hospitals, their integration into clinical practice raises several concerns for Chinese oncologists. This study aims to explore the concerns of Chinese oncologists regarding the integration of AI into clinical practice and to identify the factors influencing these concerns. A total of 228 Chinese oncologists participated in a cross-sectional web-based survey from April to June in 2023 in mainland China. The survey gauged their worries about AI with multiple-choice questions. The survey evaluated their views on the statements of "The impact of AI on the doctor-patient relationship" and "AI will replace doctors." The data were analyzed using descriptive statistics, and variate analyses were used to find correlations between the oncologists' backgrounds and their concerns. The study revealed that the most prominent concerns were the potential for AI to mislead diagnosis and treatment (163/228, 71.5%); an overreliance on AI (162/228, 71%); data and algorithm bias (123/228, 54%); issues with data security and patient privacy (123/228, 54%); and a lag in the adaptation of laws, regulations, and policies in keeping up with AI's development (115/228, 50.4%). Oncologists with a bachelor's degree expressed heightened concerns related to data and algorithm bias (34/49, 69%; P=.03) and the lagging nature of legal, regulatory, and policy issues (32/49, 65%; P=.046). Regarding AI's impact on doctor-patient relationships, 53.1% (121/228) saw a positive impact, whereas 35.5% (81/228) found it difficult to judge, 9.2% (21/228) feared increased disputes, and 2.2% (5/228) believed that there is no impact. Although sex differences were not significant (P=.08), perceptions varied-male oncologists tended to be more positive than female oncologists (74/135, 54.8% vs 47/93, 50%). Oncologists with a bachelor's degree (26/49, 53%; P=.03) and experienced clinicians (≥21 years; 28/56, 50%; P=.054). found it the hardest to judge. Those with IT experience were significantly more positive (25/35, 71%) than those without (96/193, 49.7%; P=.02). Opinions regarding the possibility of AI replacing doctors were diverse, with 23.2% (53/228) strongly disagreeing, 14% (32/228) disagreeing, 29.8% (68/228) being neutral, 16.2% (37/228) agreeing, and 16.7% (38/228) strongly agreeing. There were no significant correlations with demographic and professional factors (all P>.05). Addressing oncologists' concerns about AI requires collaborative efforts from policy makers, developers, health care professionals, and legal experts. Emphasizing transparency, human-centered design, bias mitigation, and education about AI's potential and limitations is crucial. Through close collaboration and a multidisciplinary strategy, AI can be effectively integrated into oncology, balancing benefits with ethical considerations and enhancing patient care.

Tumor Size Is Not Everything: Advancing Radiomics as a Precision Medicine Biomarker in Oncology Drug Development and Clinical Care. A Report of a Multidisciplinary Workshop Coordinated by the RECIST Working Group.

Radiomics, the science of extracting quantifiable data from routine medical images, is a powerful tool that has many potential applications in oncology. The Response Evaluation Criteria in Solid Tumors Working Group (RWG) held a workshop in May 2022, which brought together various stakeholders to discuss the potential role of radiomics in oncology drug development and clinical trials, particularly with respect to response assessment. This article summarizes the results of that workshop, reviewing radiomics for the practicing oncologist and highlighting the work that needs to be done to move forward the incorporation of radiomics into clinical trials.

Abstract PO4-18-05: Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer

Abstract Introduction- Cannabis is world’s oldest cultivated medicinal plant. It has potential applications in oncology, in reducing chronic pain, stimulating appetite, alleviating nausea/vomiting, improving overall well-being as well as its anti-cancer properties. We conducted a phase-1 dose escalation study to determine safety of pre-operative oral cannabis in breast and oral cavity squamous cell carcinoma (OC-SCC) with an intent to explore its anticancer potential in the “pre-operative” window. The primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Methodology- Primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Non-metastatic breast and OC-SCC patients planned for curative surgery were consented after thorough medical and mini-psychiatric evaluation with Brief Psychiatry Rating Scale (BPRS). The investigational product (IP) comprised of a capsule containing 2.5mg of tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD) in 100 mg monocrotolyn oil extract of dried leaves of C. sativa. The capsules were manufactured in an Ayurvedic GMP facility. The classical 3+3, phase-1 design used modified Fibonacci sequence for dose escalation, starting with 5mg THC+5mg CBD. Patients received IP once a day for 5 days after breakfast with hemodynamic and psychiatric monitoring and underwent the planned surgery on day-6. Pharmacokinetic samples were collected at predefined time-points and plasma levels of THC, 11-OH-THC, 11-COOH-THC and CBD were determined using a validated LC-MS/MS method. Tumour tissue was collected before 1st dose of cannabis and during surgery for biomarker analysis. Results- A total of 12 patients were enrolled (6-breast, 3-buccal mucosa, and 3-tongue cancers). First 3 patients completed the study without DLT at 5+5mg dose. A DLT was observed at dose level-2 (10+10mg) and therefore additional 3 patients were enrolled at the same dose. Two patients out of six at this dose had DLT (anxiety- grade-3 and somnolence- grade-2) necessitating dose de-escalation in the next cohort. At 7.5+7.5mg dose, all 3 patients tolerated the IP(MTD). Ten patients completed the study protocol. Common adverse effects were headache (2/12, grade-1), heavy head (8/12, grade-1), hypotension (2/12, grade-1 and 3), epigastric discomfort (1/12, grade-1), diarrhoea (1/12, grade-1), hyponatremia (1/12, grade-1), hypertension (1/12, grade-2), anxiety (1/12, grade-2). Pharmacokinetics of both CBD and THC was less than dose proportional. At the MTD (7.5+7.5), day-1 and day-5 AUC0-24 [median (range)] for CBD were 21.75 (12.44–41.44) ng/ml−1*h and 24.85 (13.72–35.93) ng/ml−1*h respectively. Similarly, for THC, day 1 and day 5 AUC0-24 were 11.79 (8.06–70.58) ng/ml−1*h and 68.98 (1.78 – 136.17) ng/ml−1*h, respectively. Significant accumulation of both CBD and THC was observed across all doses from day 1 to 5. A high variability in pharmacokinetics was observed for both constituents (CV Cmax = 101.26% and 117.48%; CV AUC0-24 = 102.50% and 112.37% for CBD and THC respectively. The median half-life of CBD and THC was 2.2 (1.6–10.7) and 1.9 (1.6–2.4) h respectively. There was no correlation observed between drug exposure and toxicity. There was no significant change in BPRS score before and after IP. Conclusion- We report the first phase-1 study of cannabis in breast and OC-SCC cancer in pre-operative setting for its anti-cancer potential. Biomarker analysis is awaited. MTD identified will be further explored in phase 2/3 clinical trials in breast, oral cavity, lung and pancreatic cancer with survival endpoints. Citation Format: Rajendra Badwe, Shalaka Joshi, Shiva Thiagarajan, Vikram Gota, Vaibhav Vanmali, Pallavi Daphale, Jayita Deodhar, Rohan Chaubal, Rohini Hawaldar, Jaya Chitra Aadhi, Saurabh Kumar Gupta, Delzaad Deolaliwala, Anil Bhansali, Siddhant Mistry, Satyajeet Singh, Nita Nair, Vani Parmar, Sudeep Gupta. Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-05.

Current research and future prospects of immunonutrition in gastrointestinal malignancies.

Immune nutrition, as an integral component of nutritional support therapy, has garnered significant attention and research in the treatment of gastrointestinal malignancies. Recent advancements in nutritional formulas containing components such as glutamine, omega-3 polyunsaturated fatty acids, and arginine have led to the development of what is now termed immune nutrition or pharmacological nutrition. These formulations go beyond traditional nutritional support, functioning more like nutritional supplements with pharmacological effects. Patients with gastrointestinal malignancies often experience malnutrition and metabolic disturbances, resulting in immune dysfunction, cytokine dysregulation, and endocrine abnormalities. These issues can compromise intestinal mucosal barrier function, affecting the efficacy and prognosis of anticancer therapies. Recent studies indicate that immune nutrition can modulate specific mechanisms involved in various immune and inflammatory pathways, thereby improving patients' immune status and treatment outcomes. While optimal patient selection, dosing, and timing of immune nutrition are still under investigation, its potential applications in oncology are promising. This article aims to analyze the existing evidence regarding the therapeutic benefits of immune nutrition in gastrointestinal malignancies, offering insights into its clinical standardization and application.

Abstract 521: CD45 targeted engineered toxin bodies deplete hematopoietic and malignant cells

Abstract CD45 is highly expressed on the cell surface of all nucleated hematopoietic cells, including malignant cells of B, T and myeloid lineage. CD45, a receptor tyrosine phosphatase that has important roles in antigen receptor signaling, has multiple isoforms that are differentially expressed on immune cell subsets. Targeting of CD45 with antibody-based therapies, tested in conjunction with reduced dose chemotherapy and radiation regimens, has shown promise in preclinical models and clinical trials as a conditioning therapy for bone marrow transplant (BMT), although these approaches are associated with safety limitations. A single agent, targeted conditioning method could increase patient safety and eliminate genotoxic effects associated with the conditioning regimens. Conditioning therapy by depletion of CD45 positive cells specifically has potential applications in oncology as well as non-oncologic, hematopoietic disease settings where engraftment of donor or modified stem cells could provide benefit. Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Targeted ETBs are being developed to specifically target and destroy CD45 expressing cells. ETBs targeting CD45 specifically bind to, internalize into and then trigger cell death of the target cells in vitro. ETBs have been designed using antibody fragments that recognize all isoforms of CD45. The CD45 targeted ETB has shown high potency in immortalized blood cancer cell lines of T cell, B-cell and eosinophil origin, including leukemia and lymphoma cell lines. Additionally, the ability of the CD45 targeted ETBs to deplete primary cells from healthy donors has been demonstrated. The direct cell kill activity of the CD45 targeted ETBs have the potential to deplete immune cells in the periphery and the bone marrow, as well as to deplete malignant hematological cells expressing CD45. In vivo depletion of human immune cells in murine models by CD45 targeted ETBs will be evaluated. Citation Format: Aimee Iberg, Garrett L. Robinson, Sara LeMar, Joseph D. Dekker, Jay Zhao, Hilario J. Ramos, Melissa M. Singh, Erin K. Willert. CD45 targeted engineered toxin bodies deplete hematopoietic and malignant cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 521.

QSAR modeling for prediction of binding to DNA or proteins of dermal metabolites of newly synthesized hydrazones

Introduction Over the last decade, there has been a significant increase in the scientific knowledge about cancer, which has accordingly led to the development and increase of interest in new medicines and therapeutic approaches with potential applications in oncology. Activity research and the identification of potential therapeutic and toxic effects of bexarotene-like structures underpin the development of new approaches to the treatment of a number of untreated diseases. This requires a further and in-depth study of the potential of newly synthesized compounds to produce active metabolites. Aim In view of the potential for dermal administration of bexarotene, the potential for toxic metabolism in the skin needs to be investigated. Materials and Methods For the purpose the OECD (Q) SAR Application Toolbox was used. It is a software application for evaluating the properties of chemicals based on their molecular structure. Results The application of the model for predicting metabolic changes makes it possible to assess the risk based on the chemical structure of the compounds. Conclusion The skin metabolic prediction of new hydrazones of third-generation retinoid bexarotene indicates that not one of them predicts binding to DNA or proteins.

Computational Design of New Analogues from Lyngbyastatin-2 against Epidermal Growth Factor Receptor (EGFR) through Molecular Docking

Cyanobacteria are considered as a rich source of secondary metabolites with potential applications in oncology to find out new therapeutic agents to suppress cancer. Lyngbyastatin-2 is a secondary metabolite from marine cyanobacteria and has antimicrobial and anticancer properties. It acts as an inhibitor molecule against cancer cells. In the present study, Lyngbyastatin-2 a bioactive compound from Lyngbya majuscula was selected as a ligand and four types of analogues were prepared using ChemDraw software. These analogues docked with Epidermal Growth Factor Receptor (EGFR), which is key molecule play a major role in ovarian cancer using Hex 8.0.0 molecular docking method. Among 4 analogues tested, Lyngbyastatin-2 analogue-1 (L2A1) showed high energy bonding (-618.27 KJ/mol) with EFGR molecule and considered as an effective inhibitor molecule to treat ovarian cancer based on e-values. A strong chemical interaction observed between EGFR protein and L2A1 ligand molecules and it may be leads to improve the efficiency of inhibitor. This study is the first attempt to analyze the analogues of lyngbyastatin-2 with EGFR and further in vitro, in vivo studies are required to prove its anticancer potential against ovarian cancer based on the predictions of in-silico studies.

A significant role of biomarkers in breast cancer, cervical cancer and colorectal cancer - A review

The early discovery of malignancy can altogether reduce disease mortality and spares lives. In this way, a lot of exertion has been dedicated to the investigation of new advancements to distinguish early indications of the ailment. Biomarkers have various potential applications in oncology, including peril examination, screening, differential end, an affirmation of figure, desire for response to treatment, and checking of development of illness. Malignant growth biomarkers spread an expansive scope of biochemical substances, for example, nucleic acids, proteins, sugars, little metabolites, and cytogenetic and cytokinetic parameters, just as whole tumor cells found in the body liquid. They can be utilized for hazard appraisal, finding, anticipation, and for the expectation of treatment adequacy and danger and repeat. A thorough comprehension of the pertinence of cach biomarker will be imperative for diagnosing the malady dependably yet in addition help in the decision of various restorative choices at present accessible that is probably going to profit the patients. In this review, we provide a information about late advances in disease biomarker discovery, different signalling pathways for specific tumors like breast malignancy, cervical malignancy, colorectal malignancy and finding, forecast and restorative purposes, which incorporate markers as of now in clinical practice just as different upcoming biomarkers.

Microsimulation Modeling in Oncology.

Microsimulation is a modeling technique that uses a sample size of individual units (microunits), each with a unique set of attributes, and allows for the simulation of downstream events on the basis of predefined states and transition probabilities between those states over time. In this article, we describe the history of the role of microsimulation in medicine and its potential applications in oncology as useful tools for population risk stratification and treatment strategy design for precision medicine. We conducted a comprehensive and methodical search of the literature using electronic databases-Medline, Embase, and Cochrane-for works published between 1985 and 2016. A medical subject heading search strategy was constructed for Medline searches by using a combination of relevant search terms, such as "microsimulation model medicine," "multistate modeling cancer," and "oncology." Microsimulation modeling is particularly useful for the study of optimal intervention strategies when randomized control trials may not be feasible, ethical, or practical. Microsimulation models can retain memory of prior behaviors and states. As such, it allows an explicit representation and understanding of how various processes propagate over time and affect the final outcomes for an individual or in a population. A well-calibrated microsimulation model can be used to predict the outcome of the event of interest for a new individual or subpopulations, assess the effectiveness and cost effectiveness of alternative interventions, and project the future disease burden of oncologic diseases. In the growing field of oncology research, a microsimulation model can serve as a valuable tool among the various facets of methodology available.

Low Intensity Ultrasound Can Affect Cell Behavior And Can Promote Drug Delivery

Ultrasounds (US) represent a new frontier for medical biotechnologies for their potential applications in therapy. Several studies have shown that cellular biomechanical and biophysical changes are involved in the pathogenesis of many diseases, such as cancer. For this reason, the study of the biological effects induced by exposure of both normal and neoplastic cells to the US is important to understand the effects of these changes on cellular functions and to evaluate and justify their potential applications in oncology.Aims of this study were to evaluate the effects of low‐intensity US on the proliferation, motility and differentiation of a human colon‐adenocarcinoma cell line (HT29). Moreover, we evaluated the effects of US on the delivery of oxaliplatin and on the uptake of exosomes.Cell proliferation was evaluated by MTT viability test, while cell motility using the scratch test. Cell differentiation was evaluated assessing alkaline phosphatase activity and by Western blot. Exosomes were isolated by differential centrifugation and characterized by transmission electron microscopy, Dynamic Light scatter and Western Blot to evaluate the expression of exosomal markers (CD63‐CD81‐CD9). Uptake of exosomes was evaluated by flow cytometry.All experiments were performed at four different ultrasonic frequencies (KHz), and at three acoustic intensities. Twelve hours after the treatment, the application of medium‐low intensity and frequencies US led to an increase in cell proliferation of HT29 (Fig. 1A). An inhibitory effect was observed at higher intensities. The proliferative effect was less evident at 24 hours from treatment. US exposure increased cell motility at all frequencies with a greater effect at high frequencies (Fig.1B and C). It has been described that treatment with sodium butyrate (NaBu) induces differentiation of HT29 cells, as assessed by an increased phosphatase alkaline activity, together with a reduction in the expression of the cancer stem cell marker CD133. We have shown that US treatment increases the differentiating effect of sodium butyrate by promoting alkaline phosphatase activity (Fig.2A) and CD133 reduction (Fig.2B). We also observed that USs promotes oxaliplatin‐induced cell toxicity (data not shown) and increases the uptake of exosomes likely through an ERK‐integrinβ4‐dependent mechanism (Fig. 2C and data not shown).US treatment can affect several cells functions. US could be used to promote drug as well as exosome‐mediated drug delivery. A better knowledge of the molecular mechanisms underlying the effects of US is essential for their future use in clinical practice alone and/or in combination with chemotherapeutics.Support or Funding InformationPromedica Bioelectronics srlThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hyperpolarized carbon-13 magnetic resonance spectroscopic imaging: a clinical tool for studying tumour metabolism.

Glucose metabolism in tumours is reprogrammed away from oxidative metabolism, even in the presence of oxygen. Non-invasive imaging techniques can probe these alterations in cancer metabolism providing tools to detect tumours and their response to therapy. Although Positron Emission Tomography with (18F)2-fluoro-2-deoxy-D-glucose (18F-FDG PET) is an established clinical tool to probe cancer metabolism, it has poor spatial resolution and soft tissue contrast, utilizes ionizing radiation and only probes glucose uptake and phosphorylation and not further downstream metabolism. Magnetic Resonance Spectroscopy (MRS) has the capability to non-invasively detect and distinguish molecules within tissue but has low sensitivity and can only detect selected nuclei. Dynamic Nuclear Polarization (DNP) is a technique which greatly increases the signal-to-noise ratio (SNR) achieved with MR by significantly increasing nuclear spin polarization and this method has now been translated into human imaging. This review provides a brief overview of this process, also termed Hyperpolarized Carbon-13 Magnetic Resonance Spectroscopic Imaging (HP 13C-MRSI), its applications in preclinical imaging, an outline of the current human trials that are ongoing, as well as future potential applications in oncology.

Natural Language Processing in Oncology

Natural language processing (NLP) has the potential to accelerate translation of cancer treatments from the laboratory to the clinic and will be a powerful tool in the era of personalized medicine. This technology can harvest important clinical variables trapped in the free-text narratives within electronic medical records. Natural language processing can be used as a tool for oncological evidence-based research and quality improvement. Oncologists interested in applying NLP for clinical research can play pivotal roles in building NLP systems and, in doing so, contribute to both oncological and clinical NLP research. Herein, we provide an introduction to NLP and its potential applications in oncology, a description of specific tools available, and a review on the state of the current technology with respect to cancer case identification, staging, and outcomes quantification. More automated means of leveraging unstructured data from daily clinical practice is crucial as therapeutic options and access to individual-level health information increase. Research-minded oncologists may push the avenues of evidence-based research by taking advantage of the new technologies available with clinical NLP. As continued progress is made with applying NLP toward oncological research, incremental gains will lead to large impacts, building a cost-effective infrastructure for advancing cancer care.

IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology

Interleukin- (IL-) 21 is a pleiotropic cytokine that regulates the activity of both innate and specific immunity. Indeed, it costimulates T and natural killer (NK) cell proliferation and function and regulates B cell survival and differentiation and the function of dendritic cells. In addition, IL-21 exerts divergent effects on different lymphoid cell leukemia and lymphomas, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the neoplastic lymphoid cells. Several preclinical studies showed that IL-21 has antitumor activity in different tumor models, through mechanism involving the activation of NK and T or B cell responses. Moreover, IL-21's antitumor activity can be potentiated by its combination with other immune-enhancing molecules, monoclonal antibodies recognizing tumor antigens, chemotherapy, or molecular targeted agents. Clinical phase I-II studies of IL-21 in cancer patients showed immune stimulatory properties, acceptable toxicity profile, and antitumor effects in a fraction of patients. In view of its tolerability, IL-21 is also suitable for combinational therapeutic regimens with other agents. This review will summarize the biological functions of IL-21, and address its role in lymphoid malignancies and preclinical and clinical studies of cancer immunotherapy.

Multiphoton microscopy as a diagnostic imaging modality for pancreatic neoplasms without hematoxylin and eosin stains.

Hematoxylin and eosin (H&E) staining of tissue samples is the standard approach in histopathology for imaging and diagnosing cancer. Recent reports have shown that multiphoton microscopy (MPM) provides better sample interface with single-cell resolution, which enhances traditional H&E staining and offers a powerful diagnostic tool with potential applications in oncology. The purpose of this study was to further expand the versatility of MPM by establishing the optical parameters required for imaging unstained histological sections of pancreatic neoplasms, thereby providing an efficient and environmentally sustainable alternative to H&E staining while improving the accuracy of pancreatic cancer diagnoses. We found that the high-resolution MPM images clearly distinguish between the structure of normal pancreatic tissues compared with pancreatic neoplasms in unstained histological sections, and discernable differences in tissue architecture and cell morphology between normal versus tumorigenic cells led to enhanced optical diagnosis of cancerous tissue. Moreover, quantitative assessment of the cytomorphological features visualized from MPM images showed significant differences in the nuclear–cytoplasmic ratios of pancreatic neoplasms compared with normal pancreas, as well as further distinguished pancreatic malignant tumors from benign tumors. These results indicate that the MPM could potentially serve as an optical tool for the diagnosis of pancreatic neoplasms in unstained histological sections.

Potential role of metabolomics in diagnosis and surveillance of gastric cancer.

Gastric cancer is one of the deadliest cancers worldwide, and is especially prevalent in Asian countries. With such high morbidity and mortality, early diagnosis is essential to achieving curative intent treatment and long term survival. Metabolomics is a new field of study that analyzes metabolites from biofluids and tissue samples. While metabolomics is still in its infancy, there are numerous potential applications in oncology, specifically early diagnosis. Only a few studies in the literature have examined metabolomics' role in gastric cancer. Various fatty acid, carbohydrate, nucleic acid, and amino acid metabolites have been identified that distinguish gastric cancer from normal tissue and benign gastric disease. However, findings from these few studies are at times conflicting. Most studies demonstrate some relationship of cancer cells to the Warburg Effect, in that glycolysis predominates with conversion of pyruvate to lactate. This is one of the most consistent findings across the literature. There is less consistency in metabolomic signature with respect to nucleic acids, lipids and amino acids. In spite of this, metabolomics holds some promise for cancer surveillance but further studies are necessary to achieve consistency and validation before it can be widely employed as a clinical tool.

Abstract 2193: Characterization of the aggresome targeted Q141K ABCG2/BCRP variant.

Abstract ABCG2 is a member of the G subfamily of human ABC transporters. It is an ATP-dependent protein and is a half-transporter that must dimerize for function. In various tumor cell lines, ABCG2 was involved in resistance to chemotherapy, by transporting numerous anticancer agents including tyrosine kinase inhibitors. Studies show the transporter has an important role in normal tissue protection, including the blood-brain and maternal-fetal barriers. It has also been observed that ABCG2 may play a protective role with respect to exposure to smoke or dietary carcinogens. A common variant in human ABCG2, the polymorphism Q141K, impairs expression and function, thereby reducing drug clearance and increasing the toxicity of chemotherapy and other substrate drugs. Although the activity of the Q141K variant is regularly described, biochemical data remain rare. Q141K has an impaired trafficking to cell surface compared to the WT protein and is sequestered in the aggresome. Here we characterized the Q141K and WT protein in human cells, studying post-translational modification, biochemistry, dimerization status, half-life, and endocytosis. Glycosylation and phosphorylation are equivalent, as is ATP binding and hydrolysis, and substrate binding using IAAP competition assays. Cell treatment with romidepsin, an HDAC inhibitor approved by FDA as an anticancer agent, restored the impaired variant trafficking, leading to an increase in drug efflux. The restoration of ABCG2 Q141K function has potential applications in oncology and in medicine, in improving normal tissue protection and drug elimination, as well as in cancer prevention since several carcinogens are substrates for ABCG2. Citation Format: Agnes Basseville, Suneet Shukla, Akina Tamaki, Robert Robey, Suresh V. Ambudkar, Susan E. Bates. Characterization of the aggresome targeted Q141K ABCG2/BCRP variant. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2193. doi:10.1158/1538-7445.AM2013-2193

Low-cost diffuse optical tomography for the classroom

Diffuse optical tomography (DOT) is an emerging imaging modality with potential applications in oncology, neurology, and other clinical areas. It allows the non-invasive probing of the tissue function using relatively inexpensive and safe instrumentation. An educational laboratory setup of a DOT system could be used to demonstrate how photons propagate through tissues, basics of medical tomography, and the concepts of multiple scattering and absorption. Here, we report a DOT setup that could be introduced to the advanced undergraduate or early graduate curriculum using inexpensive and readily available tools. The basis of the system is the LEGO Mindstorms NXT platform which controls the light sources, the detectors (photo-diodes), a mechanical 2D scanning platform, and the data acquisition. A basic tomographic reconstruction is implemented in standard numerical software, and 3D images are reconstructed. The concept was tested and developed in an educational environment that involved a high-school student and a group of post-doctoral fellows.

Abstract 2610: Histone deacetylase inhibitors mediate pharmacological rescue of the ABCG2 Q141K variant: Potential for therapeutics in cancer and gout

Abstract ABCG2 is an ATP-binding cassette half-transporter that has garnered interest in pharmacogenomics as a modulator of oral drug absorption, drug excretion, and drug distribution through expression at the blood-brain barrier and the maternal-fetal barrier. A single nucleotide polymorphism (SNP) C421A in ABCG2, resulting in a glutamic acid to lysine mutation at amino acid 141 (Q141K), confers impaired protein expression and function. Pharmacogenomic studies have linked the SNP to increased exposure to substrate drugs including irinotecan, topotecan, sunitinib and gefitinib. Moreover, it has been shown that 10 % of gout cases can be attributed to the Q141K variant. We have studied the biology underlying altered expression and function of the ABCG2 variant. Q141K protein was resistant to degradation by Endo H, suggesting that it was fully processed and folded. Q141K ABCG2 expression was increased by the lysosome inhibitor bafilomycin, indicating that some of the protein reached the cell surface, although at reduced levels. But the largest fraction of the Q141K variant was retained in an intracellular compartment where a part was eliminated through the proteasomal pathway while the undegraded ABCG2 accumulated in the aggresomes, as shown by colocalization of the transporter with the centrosome marker, γ-tubulin. The ability of several agents to impact ABCG2 trafficking to the cell surface was evaluated. Mitoxantrone, an ABCG2 substrate previously noted to act as a pharmacological chaperone, induced a 2-fold increase in Q141K ABCG2 expression at the cell surface but only slightly enhanced ABCG2-related efflux. Romidepsin and other histone deacetylase inhibitors (HDIs), known to increase levels of ABCG2 mRNA, were also assayed. A significant increase in total protein, surface expression, and function was seen in Q141K ABCG2 variant when exposed to various HDIs. Immunofluorescence analysis by confocal microscopy showed a dramatic shift to the plasma membrane following exposure to the HDIs, whereas the localization of α-tubulin, HDAC6 and vimentin, involved in aggresome formation and structure, were unchanged. These results support the notion that Q141K ABCG2 variant is trapped in the aggresome and that HDIs aid localization to the surface. Some supplementary experiments showed that the Q141K ABCG2 states of phosphorylation, acetylation and dimerization were unmodified after HDIs treatment, and that the chaperones BiP, Hsp70 or Hsp90 were not involved in rescue. Investigations into the HDI-mediated mechanisms are underway. In addition to non-oncologic indications, the restoration of ABCG2 function has potential applications in oncology, in improving normal tissue protection and drug elimination, as well as in cancer prevention since several carcinogens are substrates for ABCG2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2610. doi:10.1158/1538-7445.AM2011-2610

Combinatorial Biosynthesis, Metabolic Engineering and Mutasynthesis for the Generation of New Aminocoumarin Antibiotics

The aminocoumarin antibiotics novobiocin, clorobiocin and coumermycin A1 are produced by different Streptomyces strains. They are potent inhibitors of bacterial gyrase and topoisomerase IV, and novobiocin has been licensed as antibiotic for clinical use (Albamycin). They also have potential applications in oncology. The biosynthetic gene clusters of all three antibiotics have been cloned and sequenced, and the function of nearly all genes contained therein has been elucidated. Rapid and versatile methods have been developed for the heterologous expression of these biosynthetic gene clusters, and in Streptomyces coelicolor M512 as heterologous host these antibiotics were produced in yields comparable to those in the natural producer strains. lambda RED-mediated homologous recombination was used for genetic modification of the gene clusters in Escherichia coli. The phage PhiC31 attachment site and integrase functions were introduced into the cosmid backbones and employed for stable integration of the clusters into the genome of the heterologous hosts. Modification of the clusters by single or multiple gene replacements or gene deletions resulted in the formation of numerous new aminocoumarin derivatives, providing an efficient tool for the rational generation of antibiotics with modified structure. Additionally, many new antibiotics were generated by mutasynthesis experiments, i.e. the targeted deletion of genes required for the biosynthesis of a certain structural moiety of the antibiotic, and the replacement of this moiety by structural analogs which were added to the culture broth. The diversity of new structures obtained by this approach could be expanded by further genetic modifications of the gene deletion mutants, especially by expression of heterologous biosynthetic enzymes with appropriate substrate specificity.

Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS): features and potential applications in oncology

Diffusion-weighted magnetic resonance imaging (DWI) provides functional information and can be used for the detection and characterization of pathologic processes, including malignant tumors. The recently introduced concept of “diffusion-weighted whole-body imaging with background body signal suppression” (DWIBS) now allows acquisition of volumetric diffusion-weighted images of the entire body. This new concept has unique features different from conventional DWI and may play an important role in whole-body oncological imaging. This review describes and illustrates the basics of DWI, the features of DWIBS, and its potential applications in oncology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00330-008-0968-z) contains supplementary material, which is available to authorized users.