Robert Gillies

Moffitt Cancer Center · Department of Cancer Physiology

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surfac...

Acidosis is a crucial immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds CEACAM6, a cell surface prot...

Novel biomarkers that can be utilized for clinical decision support to improve patient outcomes are critically needed for ovarian cancer. At present, there are no standard of care biomarkers to inform the first-line treatment regimen (neoadjuvant chemotherapy vs. upfront surgical debulking) best suited for each patient or which patients are at the...

The extracellular pH (pHe) of solid tumors is often acidic, as a consequence of the Warburg effect, and an altered metabolic state is often associated with malignancy. It has been shown that acidosis can promote tumor progression; thus, many therapeutic strategies have been adopted against tumor metabolism; one of these involves alkalinization ther...

Simple Summary Evolution drives the initiation and progression of cancer. This is apparent in the concept of “driver mutations” that initiate cancer and observed in cells of the lineage. Less appreciated is natural selection’s role in conserving genes that are necessary for optimal cancer cell fitness. We identified highly mutated and highly conser...

“Dysregulated” metabolism is a characteristic of the cancer cell phenotype. This includes persistent use of glycolytic metabolism in normoxic environments (Warburg effect) leading to increased acid production and accumulation of protons in the interstitial space. Although often thought to be disordered, altered cancer metabolism is the outcome of i...

Clinical cancers are typically spatially and temporally heterogeneous, containing multiple microenvironmental habitats and diverse phenotypes and/or genotypes, which can interact through resource competition and direct or indirect interference. A common intratumoral evolutionary pathway, probably initiated as adaptation to hypoxia, leads to the “Wa...

Introduction Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect.” It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolyt...

Motivation Time-lapse microscopy is a powerful technique that relies on images of live cells cultured ex vivo that are captured at regular intervals of time to describe and quantify their behavior under certain experimental conditions. This imaging method has great potential in advancing the field of precision oncology by quantifying the response o...

The association of body mass index (BMI) with survival of women with ovarian cancer remains unclear due to mixed epidemiological evidence. This may be due, in part, to the fact that BMI is an imperfect measure of body fat as BMI does not distinguish weight from lean muscle versus adipose tissue. Here, we investigated the association of adiposity me...

In this study, we evaluated the feasibility of expanding tumor infiltrating lymphocytes (TIL) from surgically resected renal cell carcinoma (RCC) tumors. Tumors were collected from 43 patients undergoing surgery to remove primary kidney tumors. Tumor types included clear cell RCC (86.0%), papillary RCC (11.6%) as well as chromophobe RCC (2.3%). Tum...

Background: There are two first-line treatment recommendations for advanced ovarian cancer: i) upfront cytoreductive debulking followed by chemotherapy and ii) neoadjuvant chemotherapy prior to surgical debulking. The choice between these two treatment strategies is controversial as there are no standardized guidelines for clinical decision support...

Radiomics provides an opportunity to uncover image-based biomarkers through the conversion and analysis of standard-of-care medical images into high-dimensional mineable data. In the last decade, thousands of studies have been published on different clinical applications, novel analysis algorithms, and the stability and reproducibility of radiomics...

We present a unique database of tumor samples from 399 multiple myeloma (MM) patients, whose functional genomic landscape was assessed by integrating ex vivo drug sensitivity to 138 drugs, clinical variables, cytogenetics, mutational profiles and transcriptomes. These analyses revealed a novel MM transcriptomic topology that, when associated with e...

Malignant tumors exhibit altered metabolism resulting in a highly acidic extracellular microenvironment. Here, we show that cytoplasmic lipid droplet (LD) accumulation, indicative of a lipogenic phenotype, is a cellular adaption to extracellular acidity. LD marker PLIN2 is strongly associated with poor overall survival in breast cancer patients. Ac...

Background: Image-based biomarkers could have translational implications by characterizing tumor behavior of lung cancers diagnosed during lung cancer screening. In this study, peritumoral and intratumoral radiomics and volume doubling time (VDT) were used to identify high-risk subsets of lung patients diagnosed in lung cancer screening that are a...

Purpose: Success of clinical trials increasingly relies on effective selection of the target patient populations. We hypothesize that computational analysis of pre-accrual imaging data can be used for patient enrichment to better identify patients who can potentially benefit from investigational agents. Methods: This was tested retrospectively in s...

Background Magnetic Resonance Image guided Stereotactic body radiotherapy (MRgRT) is an emerging technology that is increasingly used in treatment of visceral cancers, such as pancreatic adenocarcinoma (PDAC). Given the variable response rates and short progression times of PDAC, there is an unmet clinical need for a method to assess early RT respo...

Breast cancer frequently metastasizes to lymphatics and the presence of breast cancer cells in regional lymph nodes is an important prognostic factor. Delineating the mechanisms by which breast cancer cells disseminate and spatiotemporal aspects of interactions between breast cancer cells and lymphatics is needed to design new therapies to prevent...

Purpose/Objective(s) Magnetic resonance image guided stereotactic body radiotherapy (MRgSBRT) is an advanced technology that may provide radiomic feature changes during treatment of adrenal lesions feasible for adaptation. Materials/Methods A prospectively maintained database was retrospectively reviewed for 24 patients with adrenal lesions who un...

Purpose Although quantitative image biomarkers (radiomics) show promising value for cancer diagnosis, prognosis, and treatment assessment, these biomarkers still lack reproducibility. In this systematic review, we aimed to assess the progress in radiomics reproducibility and repeatability in the recent years. Methods and materials Four hundred fif...

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect”. It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, i...

Rationale- Patients with indeterminate pulmonary nodules (IPNs) at risk of cancer undergo high rates of invasive, costly, and morbid procedures. Objectives: To train and externally validate a risk prediction model which combined clinical, blood, and imaging biomarkers to improve the noninvasive management of IPNs. Methods - In this prospectively co...

Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to...

p>Checkpoint blockade immunotherapy provides improved long-term survival in a subset of advanced stage NSCLC patients. Currently, predictive biomarkers of immunotherapy response are an unmet clinical need. CT and PET/CT images are routinely obtained during workup of NSCLC patients, and we hypothesize that quantitative analysis of these images (radi...

Intratumoral molecular cancer cell heterogeneity is conventionally ascribed to the accumulation of random mutations that occasionally generate fitter phenotypes. This model is built upon the “mutation-selection” paradigm in which mutations drive ever-fitter cancer cells independent of environmental circumstances. An alternative model posits spatio-...

Background Currently, only a fraction of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) experience a durable clinical benefit (DCB). According to NCCN guidelines, Programmed death-ligand 1 (PD-L1) expression status determined by immunohistochemistry (IHC) of biopsies is the only clinically approved...

Bone metastasis (BM) is a dismal complication of cancer that frequently occurs in patients with advanced carcinomas and that often manifests as an osteolytic lesion. In bone, tumor cells promote an imbalance in bone remodeling via the release of growth factors that, directly or indirectly, stimulate osteoclast resorption activity. However, carcinom...

105 Background: In the era of precision medicine, development of new cancer therapies relies strongly on effective selection of target patient population. We hypothesize that computational analysis of imaging data can be used for development of a quantitative population enrichment strategy in clinical trials and thus we aim to establish an appropri...

There is abundant evidence that the phenotype of cells the tumor at the stromal interface is distinct from the tumor cells that are within the core. Molecular phenotyping of cells at the edge show that they express higher levels of proteins associated with elevated glycolytic metabolism, including GLUT-1, HIF-1, and CA-IX. An end product of glycoly...

Many invasive cancers emerge through a years-long process of somatic evolution, characterized by an accumulation of heritable genetic and epigenetic changes and the emergence of increasingly aggressive clonal populations. In solid tumors, such as breast ductal carcinoma, the extracellular environment for cells within the nascent tumor is harsh and...

Background Immunotherapy yields survival benefit some advanced stage non-small cell lung cancer (NSCLC) patients. Since highly predictive biomarkers of immunotherapy response are an unmet clinical need, we utilized pre-treatment radiomics and clinical data to train and validate a parsimonious model associated with survival outcomes among NSCLC pati...

Approximately 50% of cancer patients eventually develop a syndrome of prolonged weight loss (cachexia), which may contribute to primary resistance to immune checkpoint inhibitors (ICI). This study utilised radiomics analysis of ¹⁸F-FDG-PET/CT images to predict risk of cachexia that can be subsequently associated with clinical outcomes among advance...

Tumor-associated macrophages are key immune cells associated with cancer progression. Here we sought to determine the role of macrophages in castration-resistant prostate cancer (CRPC) using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of CRPC tumors following macrophage depletion revealed lowe...

Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, HIF-α stabilization becomes constitutive under normoxia. We develo...

Rationale: Hypoxic regions (habitats) within tumors are heterogeneously distributed and can be widely variant. Hypoxic habitats are generally pan-therapy resistant. For this reason, hypoxia-activated prodrugs (HAPs) have been developed to target these resistant volumes. The HAP evofosfamide (TH-302) has shown promise in preclinical and early clinic...

[This corrects the article DOI: 10.1371/journal.pone.0118261.].

Tumors are highly dynamic ecosystems in which diverse cancer cell subpopulations compete for space and resources. These complex, often non-linear interactions govern continuous spatial and temporal changes in the size and phenotypic properties of these subpopulations. Because intra-tumoral blood flow is often chaotic, competition for resources may...

This study develops a novel model of a consumer-resource system with mobility included, in order to explain a novel experiment of competition between two breast cancer cell lines grown in 3D in vitro spheroid culture. The model reproduces observed differences in monoculture, such as overshoot phenomena and final size. It also explains both theoreti...

Significance Glucose is converted to energy through “fermentation” or “oxidation.” Generally, if oxygen is available, cells will oxidize glucose to CO 2 because it is more efficient than fermentation, which produces lactic acid. But Warburg noted that cancers ferment glucose at a “remarkable” rate even if O 2 is available! This “Warburg Effect” is...

Background Quantitative image analytics ("radiomics") is a powerful tool for predicting and prognosing cancer patient outcomes in response to therapy. We hypothesize that radiomic features would be useful as inclusion/exclusion criteria for patient enrichment in clinical trials and aimed to develop the appropriate framework for this analysis. Metho...

Medical imaging is the standard-of-care for early detection, diagnosis, treatment planning, monitoring, and image-guided interventions of lung cancer patients. Most medical images are stored digitally in a standardized Digital Imaging and Communications in Medicine format that can be readily accessed and used for qualitative and quantitative analys...

This review discusses the recent advances in the accelerated search for biologic meaning of radiomics signatures, as the biologic validation is gradually recognized as essential for the field to enter routine clinical practice. Radiomic analysis offers a powerful tool for the extraction of clinically relevant information from radiologic imaging. R...

Evolutionary dynamics can be used to control cancers when a cure is not clinically considered to be achievable. Understanding Darwinian intratumoral interactions of microenvironmental selection forces can be used to steer tumor progression towards a less invasive trajectory. Here, we approach intratumoral heterogeneity and evolution as a dynamic in...

External beam radiotherapy (XRT) is a widely used cancer treatment, yet responses vary dramatically among patients. These differences are not accounted for in clinical practice, partly due to a lack of sensitive early response biomarkers. We hypothesize that quantitative magnetic resonance imaging (MRI) measures reflecting tumor heterogeneity can p...

An Erratum to this paper has been published: https://doi.org/10.1038/s41576-020-00313-9.

The plasma cell malignancy multiple myeloma (MM) evolves from a pre-malignant state and remains all but incurable due to emergence of therapy resistance. Despite intensive analyses, mechanisms driving MM progression and refractory disease are poorly understood. Integrating topologic, expression and epigenetic analyses of 1,016 patient specimens, we...

Intratumour heterogeneity and phenotypic plasticity, sustained by a range of somatic aberrations, as well as epigenetic and metabolic adaptations, are the principal mechanisms that enable cancers to resist treatment and survive under environmental stress. A comprehensive picture of the interplay between different somatic aberrations, from point mut...

Rationale and Objectives Evaluate ability of radiological semantic traits assessed on multi-window computed tomography (CT) to predict lung cancer risk. Materials and Methods A total of 199 participants were investigated, including 60 incident lung cancers and 139 benign positive controls. Twenty lung window features and 2 mediastinal window featu...

Growing tumors are dynamic and nonlinear ecosystems, wherein cancer cells adapt to their local microenvironment, and these adaptations further modify the environment, inducing more changes. From nascent intraductal neoplasms to disseminated metastatic disease, several levels of evolutionary adaptations and selections occur. Here, we focus on one ex...

Purpose: To determine if quantitative features extracted from pretherapy fluorine 18 fluorodeoxyglucose (18F-FDG) PET/CT estimate prognosis in patients with locally advanced cervical cancer treated with chemoradiotherapy. Materials and methods: In this retrospective study, PET/CT images and outcomes were curated from 154 patients with locally ad...

Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) in tumor cells are stabilized in response to low levels of oxygen and induce angiogenesis to re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, however, HIF-α s...

Two major treatment strategies employed in non-small cell lung cancer, NSCLC, are tyrosine kinase inhibitors, TKIs, and immune checkpoint inhibitors, ICIs. The choice of strategy is based on heterogeneous biomarkers that can dynamically change during therapy. Thus, there is a compelling need to identify comprehensive biomarkers that can be used lon...

Currently only a fraction of patients with non-small cell lung cancer (NSCLC) experience durable clinical benefit (DCB) from immunotherapy, robust biomarkers to predict response prior to initiation of therapy are an emerging clinical need. PD-L1 expression status from immunohistochemistry is the only clinically approved biomarker, but a non-invasiv...

Background Cachexia is present in up to 50% of patients with cancer and may contribute to primary resistance to immunotherapy. Biomarkers to predict cachexia are urgently required for early intervention. Herein, we test the hypothesis that pre-treatment ¹⁸ F-FDG-PET/CT-based radiomics can be used to predict cachexia and subsequently associated with...

Background: Cancer progression is governed by evolutionary dynamics in both the tumour population and its host. Since cancers die with the host, each new population of cancer cells must reinvent strategies to overcome the host's heritable defences. In contrast, host species evolve defence strategies over generations if tumour development limits pr...

Hypoxic regions (habitats) within tumors are heterogeneously distributed and can be widely variant. Hypoxic habitats are generally pan-therapy resistant. For this reason, hypoxia-activated prodrugs (HAPs) have been developed to target these resistant volumes. The HAP evofosfamide (TH-302) has shown promise in preclinical and early clinical trials o...

Imaging is a key technology in the early detection of cancers, including X-ray mammography, low-dose CT for lung cancer, or optical imaging for skin, esophageal, or colorectal cancers. Historically, imaging information in early detection schema was assessed qualitatively. However, the last decade has seen increased development of computerized tools...

Background: Higher categories of background parenchymal enhancement (BPE) increase breast cancer risk. However, current clinical BPE categorization is subjective. Objective: Using a semi-automated segmentation algorithm, we calculated quantitative BPE measures and investigated the utility of individual features and feature pairs to significantly pr...

The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and that it occurs within lymph nodes (LNs), which are likely acidic because of low convective flow and high glucose metabolism. Here we show by in vivo fluorescence and MR imaging, tha...

Checkpoint blockade immunotherapy exhibits durable responses in a subset of advanced stage non-small cell lung cancer (NSCLC) patients. However, not all patients respond and markers that predict response to immunotherapy are still an unmet clinical need. In this study, pre-treatment quantitative image-based biomarkers (radiomics) were utilized to p...

Immunotherapy has emerged as a one of the most successful treatment approach in advanced Non-small Cell Lung Cancer (NSCLC) patients. However, only 25-50% patients obtain durable clinical benefit (DCB), and 7-43% patient may suffer from immune-related severe adverse events. Therefore robust biomarkers that are predictive of response immune-checkpoi...

Tumor habitats are phenotypically and spatially distinct intratumoral regions. Hypoxic habitats are associated with reduced accessibility of chemotherapeutics, resulting in resistance. Hypoxia targeted prodrugs (HAPs) may overcome this resistance. However, in a phase III clinical trial, the HAP evofosfamide (TH-302) did not improve survival of sarc...

Melanoma is the most lethal form of skin cancer, with a worldwide increase in incidence. Despite the increased overall survival of metastatic melanoma patients given recent advances in targeted and immunotherapy, it still has a poor prognosis and available treatment options carry diverse severe side effects. Polysaccharides from seaweed have been s...

Malignant tumors exhibit altered metabolism resulting in a highly acidic extracellular microenvironment. Adaptation to acidic conditions is a pre-requisite for tumor cells to survive and thrive and to out-compete the stroma into which they invade. Acid adaptation has been associated with chronic activation of autophagy and redistribution of the lys...

The National Lung Screening Trial (NLST) demonstrated that screening with low-dose computed tomography (LDCT) is associated with a 20% reduction in lung cancer mortality. One potential limitation of LDCT screening is overdiagnosis of slow growing and indolent cancers. In this study, peritumoral and intratumoral radiomics was used to identify a vuln...

Noninvasive diagnosis of lung cancer in early stages is one task where radiomics helps. Clinical practice shows that the size of a nodule has high predictive power for malignancy. In the literature, convolutional neural networks (CNNs) have become widely used in medical image analysis. We study the ability of a CNN to capture nodule size in compute...

Image acquisition parameters for computed tomography scans such as slice thickness and field of view may vary depending on tumor size and site. Recent studies have shown that some radiomics features were dependent on voxel size (= pixel size × slice thickness), and with proper normalization, this voxel size dependency could be reduced. Deep feature...

Quantitative imaging biomarkers (QIBs) provide medical image-derived intensity, texture, shape, and size features that may help characterize cancerous tumors and predict clinical outcomes. Successful clinical translation of QIBs depends on the robustness of their measurements. Biomarkers derived from positron emission tomography images are prone to...

Convolutional Neural Networks (CNNs) have been utilized for to distinguish between benign lung nodules and those that will become malignant. The objective of this study was to use an ensemble of CNNs to predict which baseline nodules would be diagnosed as lung cancer in a second follow up screening after more than one year. Low-dose helical compute...

Background: Five-year survival for pancreatic cancer remains low at 8%. While pancreatic cancer health disparities exist among different racial groups, these disparities have not been well investigated in the State of Florida. We aimed to investigate these disparities and hypothesized that cancer cachexia may play a role. Methods: A retrospective r...

Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only known molecular target for this drug class, where drug-induced ubiquitin-dependent degradation of "neo-substrates" such as IKAROS, AIOLOS, and...

Background: Multiparametric magnetic resonance imaging (mpMRI) has emerged as a non-invasive modality to diagnose and monitor prostate cancer. Quantitative metrics on the regions of abnormality have shown to be useful descriptors to discriminate clinically significant cancers. In this study, we evaluate the reproducibility of quantitative imaging f...

Introduction Immunotherapy has improved outcomes for patients with non-small cell lung cancer (NSCLC), yet durable clinical benefit (DCB) is experienced in only a fraction of patients. Here, we test the hypothesis that radiomics features from baseline pretreatment ¹⁸F-FDG PET/CT scans can predict clinical outcomes of NSCLC patients treated with che...

Lung cancer is the most common fatal malignancy in adults worldwide, and non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer diagnoses. Computed tomography is routinely used in clinical practice to determine lung cancer treatment and assess prognosis. Here, we developed LungNet, a shallow convolutional neural network for predicting o...

Purpose External beam radiotherapy (XRT) is a widely used cancer treatment, yet responses vary dramatically between patients. These differences are not accounted for in clinical practice, in part due to a lack of sensitive biomarkers of early response. In this work, we test the hypothesis that quantification of intratumor heterogeneity is a sensiti...

The harsh microenvironment of ductal carcinoma in situ (DCIS) exerts strong evolutionary selection pressures on cancer cells. We hypothesize that the poor metabolic conditions near the ductal center foment the emergence of a Warburg Effect (WE) phenotype, wherein cells rapidly ferment glucose to lactic acid, even in normoxia. To test this hypothesi...

Purpose: Due to the high incidence and mortality rates of lung cancer worldwide, early detection of a precancerous lesion is essential. Low-dose computed tomography is a commonly used technique for screening, diagnosis, and prognosis of non-small-cell lung cancer. Recently, convolutional neural networks (CNN) had shown great potential in lung nodul...

Checkpoint blockade immunotherapy provides improved long-term survival in a subset of advanced stage non-small cell lung cancer (NSCLC) patients. However, highly predictive biomarkers of immunotherapy response are unmet clinical need. In this study, we utilized pre-treatment clinical factors and quantitative image-based biomarkers (radiomics) to id...

Background Multiagent therapies, due to their ability to delay or overcome resistance, are a hallmark of treatment in multiple myeloma (MM). The growing number of therapeutic options in MM requires high-throughput combination screening tools to better allocate treatment, and facilitate personalized therapy. Methods A second-order drug response mod...

When cancer research advanced into the post-genomic era, it was widely anticipated that the sought-after cure will be delivered promptly. Instead, it became apparent that an understanding of cancer genomics, alone, is unable to translate the wealth of information into successful cures. While gene sequencing has significantly improved our understand...

Background Radiomic features may quantify characteristics present in medical imaging. However, the lack of standardized definitions and validated reference values have hampered clinical use. Purpose To standardize a set of 174 radiomic features. Materials and Methods Radiomic features were assessed in three phases. In phase I, 487 features were der...