Opportunities For Cancer Research Research Articles

Abstract LB333: Improved spatially resolved single-cell transcriptomic imaging in archival tissues with MERSCOPE

Abstract The advent of spatial transcriptomics has enabled a revolution in how complex tissues are studied. However, samples with lower quality RNA due to degradation, protein crosslinking, or high RNase content remain challenging for spatial transcriptomic measurement. In particular, formalin fixed, paraffin embedded (FFPE) tissues are the most widely used sample types in clinical and molecular diagnosis, yet they are notoriously difficult for single-cell transcriptomic analysis. To accurately profile the gene expression in FFPE samples in situ, a spatial transcriptomics technique with high detection efficiency and single molecule resolution is required. The Vizgen® MERSCOPE® Platform for spatial genomics is built on Multiplexed Error Robust in situ Hybridization (MERFISH) technology and directly profiles the transcriptome of intact tissues with high sensitivity in high-quality samples. Here we present an updated workflow to perform MERFISH in low and high-quality samples. We demonstrated its application in more than 5 FFPE sample types from mouse and human, including archival samples. For each tissue type, hundreds of thousands of cells were captured using the updated MERSCOPE Platform workflow, generating 100s million counts and their spatial information for profiled genes in each sample. The updated workflow involves streamlined sample preparation and chemistry optimization to improve sensitivity. MERSCOPE accurately profiled gene expression in situ and mapped cell types in archival human samples across a range of low and high RNA qualities. We compared the performance of MERSCOPE imaging using the updated protocol to the previous version and observed a significant increase in gene counts per 100 micron2 of tissue. We also demonstrated increased reproducibility between replicates with the streamlined workflow and chemistry. Furthermore, we demonstrated the updated workflow is compatible with simultaneous protein-based cell boundary staining. Finally, we constructed a spatially resolved single-cell atlas across low-quality archival breast and lung tumor types, mapped and cataloged different cell types within the tumor microenvironment, and systematically characterized the gene expression among cells. Spatially resolved transcriptomic profiling of low-quality samples at single-cell level provides enormous opportunities in cancer research. These improvements will enable new genomic inquiries into previously intractable tissues like FFPE, leading to new biological insights into cancer progression. Citation Format: Jiang He, Bin Wang, Justin He, Renchao Chen, Benjamin Patterson, Sudhir Tattikota, Timothy Wiggin, Lizi Maziashvili, Peter Reinhold, Manisha Ray, George Emanuel. Improved spatially resolved single-cell transcriptomic imaging in archival tissues with MERSCOPE [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB333.

In vitro model of human mammary gland microbial colonization (MAGIC) demonstrates distinctive cytokine response to imbalanced human milk microbiota.

Despite the established concept of the human mammary gland (MG) as a habitat with its own microbiota, the exact mechanism of MG colonization is still elusive and a well-characterized in vitro model would reinforce studies of the MG microbiota development. We aimed to establish and characterize an in vitro cell model for studying MAmmary Gland mIcrobial Colonization (MAGIC) model. We used the immortalized cell line MCF10A, which expresses the strong polarized phenotype similar to MG ductal epithelium when cultured on a permeable support (Transwell). We analyzed the surface properties of the MAGIC model by gene expression analysis of E-cadherin, tight junction proteins, and mucins and by scanning electron microscopy. To demonstrate the applicability of the model, we tested the adhesion capability of the whole human milk (HM) microbial community and the cellular response of the model when challenged directly with raw HM samples. MCF10A on permeable supports differentiated and formed a tight barrier, by upregulation of CLDN8, MUC1, MUC4, and MUC20 genes. The surface of the model was covered with mucins and morphologically diverse with at least two cell types and two types of microvilli. Cells in the MAGIC model withstood the challenge with heat-treated HM samples and responded differently to the imbalanced HM microbiota by distinctive cytokine response. The microbial profile of the bacteria adhered on the MAGIC model reflected the microbiological profile of the input HM samples. The well-studied MAGIC model could be useful for studies of bacterial attachment to the MG and for in vitro studies of biofilm formation and microbiota development.IMPORTANCEThe MAGIC model may be particularly useful for studies of bacterial attachment to the surface of the mammary ducts and for in vitro studies of biofilm formation and the development of the human mammary gland (MG) microbiota. The model is also useful for immunological studies of the interaction between bacteria and MG cells. We obtained pioneering information on which of the bacteria present in the raw human milk (HM) were able to attach to the epithelium treated directly with raw HM, as well as on the effects of bacteria on the MG epithelial cells. The MAGIC cell model also offers new opportunities for research in other areas of MG physiology, such as the effects of bioactive milk components on microbial colonization of the MG, mastitis prevention, and studies of probiotic development. Since resident MG bacteria may be an important factor in breast cancer development, the MAGIC in vitro tool also offers new opportunities for cancer research.

Cancer: Its Symptoms, Challenges and Opportunities in Research in India: A Review

Cancer is uncontrolled division of the cells and has to capability to evade central endogenous control mechanism and as result of this spread to the surrounding tissue. The accumulating knowledge about development and progression of cancer can be used to develop more precise diagnostic and more effective and or less toxic cancer therapies. It is the second leading cause of death worldwide. After cardiac disease cancer has emerged as an important cause of mortality and morbidity in India. In 2019 annual cases grew by 23.6 million and 10 million deaths worldwide. The article compiled with the objective to know regarding the challenges and opportunities in cancer research in India.

MHealth: experiences and opportunities for cancer research in Mexico.

Not available.

The topology of data: opportunities for cancer research.

MotivationTopological methods have recently emerged as a reliable and interpretable framework for extracting information from high-dimensional data, leading to the creation of a branch of applied mathematics called Topological Data Analysis (TDA). Since then, TDA has been progressively adopted in biomedical research. Biological data collection can result in enormous datasets, comprising thousands of features and spanning diverse datatypes. This presents a barrier to initial data analysis as the fundamental structure of the dataset becomes hidden, obstructing the discovery of important features and patterns. TDA provides a solution to obtain the underlying shape of datasets over continuous resolutions, corresponding to key topological features independent of noise. TDA has the potential to support future developments in healthcare as biomedical datasets rise in complexity and dimensionality. Previous applications extend across the fields of neuroscience, oncology, immunology and medical image analysis. TDA has been used to reveal hidden subgroups of cancer patients, construct organizational maps of brain activity and classify abnormal patterns in medical images. The utility of TDA is broad and to understand where current achievements lie, we have evaluated the present state of TDA in cancer data analysis.ResultsThis article aims to provide an overview of TDA in Cancer Research. A brief introduction to the main concepts of TDA is provided to ensure that the article is accessible to readers who are not familiar with this field. Following this, a focussed literature review on the field is presented, discussing how TDA has been applied across heterogeneous datatypes for cancer research.

Abstract PL01-03: Ancestry and cancer disparities: Genomic sequencing in diverse populations

Abstract Over the past decade, genomic advancements have afforded tremendous opportunities in cancer research; including characterization of gene expression networks that distinguish tumor types, and the resolution of genomic structure that drives tumor growth and treatment outcomes. Despite these advances, disparities in cancer outcomes persist as does our paucity in data to understand the breadth of diversity in tumor traits across populations. Most of the data that defines our current understanding of cancer genetics was generated within the context of mainly European ancestry. This bias is partially due to geographic convenience of recruitment within the proximity of the institutions that generate these data elements. This type of systemic bias has perpetuated disparities of already marginalized racial minority populations, compared to their European race-group counterparts. However, international consortia have led to new insights and access, with strategic recruitment and study designs that harness population genetic diversity. Germline genomic investigations have uncovered ancestral susceptibilities that are either due to prevalence of ancestry-specific risk alleles or ancestrally/evolutionarily conserved modifiers of molecular pathways that prime development of certain tumor subtypes. Tumor/somatic genomics have repeatedly uncovered gene signatures that reflect thematic differences in tumor immune microenvironment as well as copy number variations, which are more recently being investigated with high-resolution technologies in imaging and genomic architecture, linked to genetic ancestry. As we turn our lens to the genomic context of population diversity, we are realizing novel opportunities to develop transformative precision medicine applications. Specifically, for this plenary presentation, we will highlight the transition of GWAS studies to functionalize genetic ancestry differences, enhanced with inclusion of ancestral populations, as opposed to the traditional filtration of these features. We will overview the newest concepts of complex germline and somatic architecture in the context of disparities and how these are determining the mysterious function of genomic associations identified as population-private risk across multiple ethnicities; including Asian, Latin American and African ancestry clades. We will demonstrate the utility of Whole Genome Sequencing in the clinical genetics space to mitigate disparities by characterizing the pathological features (Genomic Phenotypes) of the insidious Variables of Unknown Significance (VUS) and how these findings can fast-track minority access to alternative treatments. These data will ultimately improve our interpretations of overall cancer risk and risk of recurrence test results and recalibrate risk models. Lastly, we give a call to action that resounds the importance of including not only the genetic history (ancestry) but also the social history (self-reported race) of cancer patients and how this multidisciplinary approach will unlock our understanding of the drivers of aggressive tumor biology and be a catalyst for implementation of customized prevention and survivorship interventions. Only with the “Power of Inclusion” can we hope to traverse the breadth of disparities and make leaps of progress in cancer research and treatment. Citation Format: Melissa B. Davis. Ancestry and cancer disparities: Genomic sequencing in diverse populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL01-03.

Creating opportunities in cancer research

Cancer research has undergone transformational changes over the past several decades. On the occasion of the 20th anniversary of the establishment of the NCI Center for Cancer Research, we highlight some elements that enable successful institutional approaches to solving the most pressing problems in cancer research.

Abstract PO-020: Cancer Research Opportunities for Youth at Yale: Advancing the diversification of the cancer research pipeline

Abstract Background: The goal of the Cancer Research Opportunities for Youth (CROY) at Yale Program is to advance the diversification of the cancer research pipeline by providing young people from groups traditionally underrepresented in cancer research with hands–on experience, mentoring, and the opportunity to collaborate with Yale Cancer Center (YCC) research teams. Our purpose is to report on researcher and student experiences and lessons learned in this unique training program. Methods: Pre- and post- survey data were collected from researchers and scholars in each year of the program, 2017-2020. Results: Scholars were placed in five of six YCC Research Programs: Cancer Prevention and Control; Developmental Therapeutics; Genomics, Genetics and Epigenetics; Radiobiology and Radiotherapy; and Virus and Other Infection-associated Cancers. With 2 years minimum per student, available slots decreased over time. Averaging 26 applicants per year, the acceptance rate was 18% (14/78). In year 04, with COVID-19 pandemic, 2 returning students were offered remote internships in the community research. Scholar Characteristics: Over the 4 years of CROY, we trained 14 scholars, with 36% (5/14) entering 10th grade, 50% (7/14) entering 11th grade, and 2 (14%) entering seniors. 43% (6/14) of scholars were female. Six (43%) scholars self-identified as African American/Black, 50% (n = 6) were Hispanic/Latinx, and 1 (7.1%) student was Asian and a recent immigrant. Ten of 14 (71%) qualified for free school lunch, a proxy for socioeconomic hardship. Pre- Post Scholar survey results: Students reported being supported by their research teams, learning new research skills, and feeling comfortable asking questions of trainers. With few exceptions, the internship experience resulted in higher scores (positive impact) on the post survey compared with the baseline for scholars. The largest changes (10% increase on a 10 point scale): 1) “I would consider a career in cancer research”, and 2) “I am confident working in a lab”, whereas there was a 4% decrease on 2 items: 1) “I am confident doing a literature search”, and 2) “I consistently do my best at school”. Results from investigator data were positive, with some researchers expecting students to have more experience before joining their labs. Lessons Learned: 1) Logistical constraints included shortened summer holiday in northeast, US.; 2) Researchers vary in preparedness for younger students; pre- internship training of investigators may help manage expectations; 3) Timely communication with HS students is challenging; texting and parental involvement were helpful; 4) Retention of scholars is complicated by extraordinary challenges associated with social determinants, including death of parents, living in foster care, leaving program to help with family business, and financial issues that limited college choice. Conclusion: Programs aimed at young adults underrepresented in research require flexibility in setting expectations and organizational structure. Citation Format: Beth Anne Jones, Rachel Clare, Steven J. Parra, Sakinah Suttiratana, Hannah Behringer. Cancer Research Opportunities for Youth at Yale: Advancing the diversification of the cancer research pipeline [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-020.

Circulating Tumor Cells: State-of-the-art Update on Technologies and Clinical Applications.

Circulating tumor cells represent rare events in the peripheral blood of patients with cancer that can provide insight into tumor biology. CTC enumeration, isolation, and analysis represent liquid biopsy approaches whose role in the management of patients with cancer continues to evolve in the era of precision medicine. This review presents an overview of technologies central to studying CTCs. Technologies for CTC isolation can be divided into two categories: label-dependent and label-independent. Label-dependent techniques utilize biological properties such as cell surface proteins, while label-independent techniques utilize distinctive physical properties such as cell size, density, and plasticity. Advances in microfluidics designs as well as hybrid combinations of label-dependent and label-independent techniques have resulted in unprecedented improvements in CTC isolation, permitting not only the detection and enumeration of these rare events but also providing the means for studying them and exploring them as a new dimension of cancer biomarkers. With advances in tools for isolating and studying CTCs in hand, questions regarding the clinical utility of CTC enumeration in peripheral blood, detection of CTC-associated biomarkers, and analysis of dynamic changes in CTCs during the course of cancer therapy represent exciting new opportunities for cancer research.

An electrochemical biosensor to distinguish between normal and cancer cells based on monitoring their acidosis using gold-coated silicon Nano-roughened electrode

One of the most interesting fields of research in cancer diagnosis is tracing the relation between extracellular media and cancer progression. Detecting the secreting contents of the cells and translating these molecular identifications into label-free recognizable patterns would open new opportunities in cancer research. Electrochemical responses are in the range of most attractive sensing mechanisms especially in biochemical approaches. Perturbed ionic exchanges as a known biochemical function of cancer cells presented a strong correlation with the pH of the tumor microenvironment. Different ionic activities detected by an electrochemical bio-sensing system in the malignant and normal cells in the presence of acidic ambient were our main results presented in this research. Herein, silicon Nano-roughened substrate as a well-known electrochemical interface was applied in the construction of the biosensor. Viability rate as well as apoptotic factors involving in cancer progression were assessed by biochemical assays in normal (MCF10A) and cancer (MCF7 and MDA-MB468) breast cells. Our findings demonstrated that pH-based electrochemical responses were matched with the results obtained from the biological analyses of both normal and malignant cells. Induction of acidosis in the cells followed by monitoring their electrochemical responses would be a new trend in microenvironment based cancer investigation.

Fluorescent polydopamine nanoparticles as a probe for zebrafish sensory hair cells targeted in vivo imaging

Fluorescent polydopamine nanoparticles (FPNPs) are prepared via the ethylenediamine (EDA)-induced degradation of as-prepared non-fluorescent polydopamine (PDA) and used for targeted bioimaging. The reductive treatment of PDA in the presence of EDA yields fluorescent precipitates, inspiring us to seek various biological approaches to preparing FPNPs with excellent optical and biocompatible properties. Moreover, we firstly found that FPNPs selectively label neuromast hair cells in the lateral line of zebrafish, their applications as a reliable fluorescent indicator to investigate the neuromast hair cells, to in turn determine the viability of hair cells, was demonstrated. FPNPs also provided a minimal toxicity enable to assay the number of functional hair cells per neuromast in live animals as development proceeds. Upon combined incubation with TO-PRO-3, a well-established hair cell marker, all hair cells that were rapidly labeled with FPNPs were observed to be also completely labeled with the TO-PRO-3, labeling hair cells in neuromasts positioned in the supraorbital, otic and occipital lateral line as well as in posterior lateral line of living zebrafish larvae. Their potential efficacy for biological applications was demonstrated by their excellent optical and biocompatible properties, offering new opportunities in cancer research, real-time monitoring of stem cell transplantation and other cell-based therapies.

Rethinking cancer: current challenges and opportunities in cancer research

ABSTRACTCancer therapeutics currently have the lowest clinical trial success rate of all major diseases. Partly as a result of the paucity of successful anti-cancer drugs, cancer will soon be the leading cause of mortality in developed countries. As a disease embedded in the fundamentals of our biology, cancer presents difficult challenges that would benefit from uniting experts from a broad cross-section of related and unrelated fields. Combining extant approaches with novel ones could help in tackling this challenging health problem, enabling the development of therapeutics to stop disease progression and prolong patient lives. This goal provided the inspiration for a recent workshop titled ‘Rethinking Cancer’, which brought together a group of cancer scientists who work in the academic and pharmaceutical sectors of Europe, America and Asia. In this Editorial, we discuss the main themes emerging from the workshop, with the aim of providing a snapshot of key challenges faced by the cancer research community today. We also outline potential strategies for addressing some of these challenges, from understanding the basic evolution of cancer and improving its early detection to streamlining the thorny process of moving promising drug targets into clinical trials.

Electrochemical approach for monitoring the effect of anti tubulin drugs on breast cancer cells based on silicon nanograss electrodes

One of the most interested molecular research in the field of cancer detection is the mechanism of drug effect on cancer cells. Translating molecular evidence into electrochemical profiles would open new opportunities in cancer research. In this manner, applying nanostructures with anomalous physical and chemical properties as well as biocompatibility would be a suitable choice for the cell based electrochemical sensing. Silicon based nanostructure are the most interested nanomaterials used in electrochemical biosensors because of their compatibility with electronic fabrication process and well engineering in size and electrical properties. Here we apply silicon nanograss (SiNG) probing electrodes produced by reactive ion etching (RIE) on silicon wafer to electrochemically diagnose the effect of anticancer drugs on breast tumor cells. Paclitaxel (PTX) and mebendazole (MBZ) drugs have been used as polymerizing and depolymerizing agents of microtubules. PTX would perturb the anodic/cathodic responses of the cell-covered biosensor by binding phosphate groups to deformed proteins due to extracellular signal-regulated kinase (ERK1/2) pathway. MBZ induces accumulation of Cytochrome C in cytoplasm. Reduction of the mentioned agents in cytosol would change the ionic state of the cells monitored by silicon nanograss working electrodes (SiNGWEs). By extending the contacts with cancer cells, SiNGWEs can detect minor signal transduction and bio recognition events, resulting in precise biosensing. Effects of MBZ and PTX drugs, (with the concentrations of 2 nM and 0.1 nM, respectively) on electrochemical activity of MCF-7 cells are successfully recorded which are corroborated by confocal and flow cytometry assays.

Paradoxes in Carcinogenesis Should Spur New Avenues of Research: An Historical Perspective

Abstract A major obstacle to winning the war on cancer is a lack of understanding of how cancer develops. The dominant theory for the last 50 years has been the somatic mutation theory (SMT), which says that cancer arises directly from a sequence of genetic changes on a cell that leads to its proliferation. The alternative tissue organization field theory (TOFT) says that cancers arise from a disruption of cell communication needed to maintain normal tissue architecture. A historical background places these theories into perspective. Various experimental results are paradoxical under SMT, but readily explained under TOFT, suggesting paradigm instability. These paradoxical results offer new opportunities for cancer research.

Imaging Cancer in Mice by PET, CT, and Combined PET-CT.

The possibility of imaging tumors in live mice has opened new opportunities for cancer research, particularly regarding the ability to perform longitudinal studies in combination with a therapeutic intervention. Here, we detail methods to optimize visualization of murine tumors by positron emission tomography (PET), computed tomography (CT), and combined PET-CT. Curr. Protoc. Mouse Biol. 1:85-103. © 2011 by John Wiley & Sons, Inc.

Shaking Up Cancer Clinical Trials: An Interview With John Mendelsohn, M.D.

A recent report from the Institute of Medicine (IOM) said the National Cancer Institute’s cooperative group program is not prepared to meet current opportunities in cancer research despite its contributions to past progress. The IOM criticized the program for being slow, bureaucratic, inefficient, and unproductive. Simultaneously, the American Society of Clinical Oncology (ASCO) published a survey showing that oncologists are planning to limit, or are considering limiting, their participation in trials because NCI’s reimbursement is inadequate. Although they were issued in April, the two reports continue to reverberate throughout the cancer community. John Mendelsohn, M.D. , president of the M. D. Anderson Cancer Center in Houston and chair of the IOM panel, spoke about the recommendations in press briefi ngs and oral sessions at the annual meetings of ASCO and the American Association for Cancer Research. Outgoing NCI director John Niederhuber, M.D., who commissioned the report, went further. He recommended to the National Cancer Advisory Board in June that the cooperative group system be scrapped and replaced by a system based on the NCI-funded cancer centers. Richard Schilsky, M.D., a longtime leader in the cooperative group system and an IOM panelist, responded publicly that this was not a good idea and that all the IOM recommendations should be implemented soon. Cooperative groups continued to be in the oncology news with an announcement that three of the groups would merge some administrative functions — a development in line with IOM recommendations but predating the report, they said. And incoming NCI director Harold Varmus, M.D., in his fi rst town hall meeting with staff, named the clinical trials system as one of several areas that were “obviously dysfunctional” and needed repair. Meanwhile, innovative trial designs, based on patient biomarkers, are attracting attention as ways to streamline and speed up trials ( see accompanying news stories). I interviewed Mendelsohn in May about the IOM report — A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program — and what he thinks needs to be done to improve the cancer clinical trial system. JN: The IOM report was issued at the same time as the ASCO survey. With a new director scheduled to be appointed, was the timing a coincidence? JM: The IOM report was commissioned a year ago by NCI director Dr. John E. Niederhuber, over concerns about the program’s ability to maintain the progress they have produced. I hope that when the new director addresses the report, he will see it as helpful and accept our recommendations. It may allow the new head of the NCI to get cracking and not waste time with another review. [ Editor’s note: the interview occurred before a new director was named. ] JN: Your report found that the NCI’s review process delays launching a clinical trial. The NCI reports that 56% of phase III clinical trials took more than 2 years to start. How can the speed and effi ciency of the design, launch, and conduct of clinical trials be improved? JM: The entire process must be streamlined so we can implement ways to do it more effi ciently. The NCI has redundant review procedures that add to reviews by the cooperative groups, the intergroup scientifi c review committee, the Food and Drug Administration [FDA], etc. As modifi cations are made, protocols must be recycled again and again. All of this only serves to delay the launch of a clinical trial. The prime task should be to get an innovative, high-priority trial approved in a shorter period of time with adequate reimbursement for time and effort, adopting best practices for effi cacy and safety. Right now, the NCI, the FDA, the cooperative groups, pharmaceutical and biotech companies, and academic and community medical groups are looking at the shared goal of developing new drugs against cancer through different lenses with different agendas. If we could get all of the various people who have an interest in clinical trials and lock them in a room, we’d get lots of work done quickly and have a better trial. We are all going to have to do some giving because there is such a great opportunity today to exploit our capacity to select new drugs and antibodies that target the genetic abnormalities expressed in an individual patient’s cancer.

Perspectives on the development of imatinib and the future of cancer research

Imatinib: a personal history I am incredibly fortunate. To receive an award from the Lasker Foundation, with its preeminent jury, is indeed an honor. But the greatest reward is seeing patients every week in clinic who have benefitted from my work. The life expectancy of these patients was originally three to five years. They are now leading active and productive lives, and many have been with me for over ten years. My desire to pursue a career in oncology began when I was a medical student, when I took an elective course on the history of chemotherapy. We learned about the cure of childhood leukemia with combination chemotherapy and about the contributions of pioneers such as Sidney Farber and Lasker laureates Emil Frei and Emil Freireich. Despite these breakthroughs, I imagined there had to be a better way to treat cancer, and I wrote in my final essay that only through a molecular understanding of cancer would we be able to more rationally treat the disease. Even though the prognosis for most cancers was quite poor, it seemed to me that there would be great opportunities in cancer research over the next 20 to 30 years, and I wanted to be a part of this. When I started my training in oncology at Dana-Farber Cancer Institute, we spent most of our time trying to extend our patients’, lives, but our tools were limited. We had 5-flurouracil for colon cancer, doxorubicin (Adriamycin) and one of the first targeted cancer agents, tamoxifen, for breast cancer. For prostate cancer, we were testing long-acting androgen antagonists as an alternative to castration. As for patients battling chronic myeloid leukemia (CML), we dreaded each visit. We checked blood counts, looking for the inevitable signs of progression of the disease to a fatal and untreatable acute leukemia, knowing we would have to deliver harsh news. With this background, I decided to pursue a laboratory career and pledged to continue the work until I was confident that I had something to contribute that was a vast improvement over what was then available. In early 1985, I met with Thomas Roberts at Dana-Farber on the advice of George Khoury1. Despite my limited lab background, Tom was willing to take a chance on his first MD postdoctoral fellow. I entered a lab filled with incredible postdocs and graduate students who became my mentors and friends. This group included Helen Piwnica-Worms, David Kaplan, Michael Corbley, Tony West, Connie Gee, Harvey Mamom, Kenneth Wood and David Pallas (Fig. 1). All were extremely patient and helpful in advising a relatively green trainee. We also worked closely with the labs of David Livingston and Charles Stiles and had an ongoing collaboration with Lewis Cantley. It was an exciting time in Tom’s lab, as many insights into kinase signaling pathways were being discovered. My initial project was to work Brian J. Druker is an Investigator of the Howard Hughes Medical Institute, JELD-WEN Chair of Leukemia Research, and Director of the Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, USA. e-mail: drukerb@ohsu.edu

Common Polymorphism in the Phosphatase PHLPP2 Results in Reduced Regulation of Akt and Protein Kinase C

PHLPP2 (PH domain leucine-rich repeat protein phosphatase 2) terminates Akt and protein kinase C (PKC) activity by specifically dephosphorylating these kinases at a key regulatory site, the hydrophobic motif (Ser-473 in Akt1). Here we identify a polymorphism that results in an amino acid change from a Leu to Ser at codon 1016 in the phosphatase domain of PHLPP2, which reduces phosphatase activity toward Akt both in vitro and in cells, in turn resulting in reduced apoptosis. Depletion of endogenous PHLPP2 variants in breast cancer cells revealed the Ser-1016 variant is less functional toward both Akt and PKC. In pair-matched high grade breast cancer samples we observed retention of only the Ser allele from heterozygous patients (identical results were observed in a pair-matched normal and tumor cell line). Thus, we have identified a functional polymorphism that impairs the activity of PHLPP2 and correlates with elevated Akt phosphorylation and increased PKC levels.

Functional imaging for assessment of therapy.

Functional imaging signals such as the regional uptake of the radiolabelled glucose analogue fluorodeoxyglucose (FDG), which can be noninvasively defined by positron emission tomography (PET), are suitable for the assessment of the response of tumour tissue to therapeutic interventions [1]. Therefore, in addition to its documented value in diagnosing tumour tissue, FDG-PET will have a major clinical impact through its role in therapy management. This prediction is supported by the fact that relatively little health care expenditure is used for the diagnosis of cancer compared with the large financial resources directed towards therapy. Imaging methods that will reduce the cost of therapy will help to manage oncological patients cost effectively. In addition to its promising clinical applications, PET also has an important role in clinical research. Based on the recommendations of the Director of the NCI for the fiscal budget of 2001, five particular opportunities for cancer research were identified. ‘‘Imaging of cancer’’ was chosen as the second most important. Closely related to this topic was ‘‘defining the signatures of cancer cells’’, which was also considered to be of future significance. The development of imaging signals to characterize tumour tissue and to define possible targets for therapy will emerge as an important academic challenge for the imaging community in the foreseeable future (see www. cancer.gov — budget section). However, PET is only one of many new imaging modalities being developed. Morphological imaging with CT and magnetic resonance tomography (MR) has advanced significantly over recent years, yielding excellent temporal and spatial resolution. At the same time, new imaging approaches have been introduced to provide a variety of functional signals, which can be used for non-invasive tissue characterization. Such signals include the qualitative and quantitative assessment of tissue perfusion, metabolism and signal transmission. New targets for imaging probes will emerge as our knowledge of biology increases. The identification of specific antigen and protein expression in tumour tissue will provide new stimuli for the visualization of tumour biology in vivo [2, 3]. Finally, as gene therapy becomes a clinical reality, there is a need for methods to monitor the efficacy of transfection as well as to assess protein expression, and the role of imaging is likely to expand [4]. As we progress from structural to biological imaging, several methods are in competition (Figure 1). The tracer approach using radioactive labelled compounds excels because of its high sensitivity. Picomolar concentrations of radiolabelled molecules can be detected in tissue, which compares favourably with MRI. However, the tracer approach is limited in specificity since radioisotopes can be separated from the labelled molecules by metabolic processes altering the regional distribution of the radioactivity. Optical imaging using fluorescence probes is most likely to compete in the future for the visualization of biological processes. However, the clinical application of this approach may be limited by the distance light can penetrate tissue [5]. The PET technology currently available produces tomographic images of the entire body, allowing visualization of regional metabolic processes with high spatial resolution (Figure 2). As a marker for glucose utilization, FDG provides high biological contrast between normal and malignant tissue. It has been known for many years that tumour tissue exhibits increased glucose uptake and glycolytic activity. This exciting new technology has gained wide clinical acceptance for diagnosing and localizing tumour tissue [6, 7]. However, its role in monitoring therapy is just now emerging. In this paper I will concentrate on the possible role of this modality to assist therapy in patients with cancer. What are the hypotheses that support the role of PET in therapy monitoring? Firstly, accurate staging of the tumour is necessary and will significantly influence the choice of therapy. Secondly, metabolic signals, such as FDG uptake, can be used to assess objectively the effect on therapy and tissue biochemistry. Several studies have shown that a decrease in metabolic activity precedes a change in tumour size [8]. Thirdly, it is necessary to identify residual tumour viability after therapy to define prognosis and to stratify the use of subsequent chemotherapy and radiotherapy. Finally, individual tissue characterization leading to the identification of therapy targets by The British Journal of Radiology, 75 (2002), S67–S73 E 2002 The British Institute of Radiology