Downloadable Publications

Comparing machine learning algorithms for predicting ICU admission and mortality in COVID-19

Subudhi S, Verma A, Patel AB, Hardin CC, Khandekar MJ, Lee H, McEvoy D, Stylianopoulos T, Munn LL, Dutta S, Jain RK

As predicting the trajectory of COVID-19 is challenging, machine learning models could assist physicians in identifying high-risk individuals. This study compares the performance of 18 machine learning algorithms for predicting ICU admission and mortality among COVID-19 patients. Using COVID-19 patient data from the Mass General Brigham (MGB) Healthcare database, we developed and internally validated models using patients presenting to the Emergency Department (ED) between March-April 2020 (n = 3597) and further validated them using temporally distinct individuals who presented to the ED between May-August 2020 (n = 1711). We show that ensemble-based models perform better than other model types at predicting both 5-day ICU admission and 28-day mortality from COVID-19. CRP, LDH, and O2 saturation were important for ICU admission models whereas eGFR <60 ml/min/1.73 m2, and neutrophil and lymphocyte percentages were the most important variables for predicting mortality. Implementing such models could help in clinical decision-making for future infectious disease outbreaks including COVID-19.



Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas

Amoozgar Z, Kloepper J, Ren J, Tay RE, Kazer SW, Kiner E, Krishnan S, Posada JM, Ghosh M, Mamessier E, Wong C, Ferraro GB, Batista A, Wang N, Badeaux M, Roberge S, Xu L, Huang P, Shalek AK, Fukumura D, Kim HJ, Jain RK

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.



In silico dynamics of COVID-19 phenotypes for optimizing clinical management 

Voutouri C, Nikmaneshi MR, Hardin CC, Patel AB, Verma A, Khandekar MJ, Dutta S, Stylianopoulos T, Munn LL, Jain RK

A distinctive feature of COVID-19 is its extreme heterogeneity—illness ranges from minimally symptomatic to life threatening. Heterogeneity results from a poorly understood combination of patient factors, viral dynamics, antiviral and immune modulating therapies, and dynamics of the innate and adaptive immune responses. In order to better understand clinical heterogeneity and optimal treatment, we developed a comprehensive mathematical model incorporating elements of the innate and adaptive immune responses, the renin−angiotensin system (which the virus exploits for cellular entry), rates of viral replication, inflammatory cytokines, and the coagulation cascade. Our model reveals divergent treatment responses and clinical outcomes as a function of comorbidities, age, and details of the innate and adaptive immune responses which can provide a framework for understanding individual patients’ trajectories.



Physical Traits of Cancer 

Hadi T. Nia, Lance L. Munn, Rakesh K. Jain

The biological and physical properties of tumors contribute to their growth and to treatment outcome. Although intense research efforts have helped to delineate cancer biology, the physics of cancer has only emerged in relatively recent times as a key area of research. Nia et al. reviewed the physical features that are common to tumors and that limit successful treatment: solid stresses, interstitial fluid pressure, stiffness (rigidity), and architecture and organization of tumor constituents. The authors provide a conceptual framework and discuss the origins of these distinct physical traits of cancer and how they enable and synergize with aberrant cancer biology to fuel cancer initiation, progression, immune evasion, and treatment resistance.




Vascular regulation of antitumor immunity

Immunotherapy with immune checkpoint blockers (ICBs) has revolutionized cancer treatment. Unfortunately, ICB therapy usually benefits <15% of patients and causes immune-related adverse events in a substantial number of patients. Another immunotherapy—engineered chimeric antigen receptor (CAR) T cells that specifically target tumor-associated antigens—has transformed the treatment of multiple hematological cancers and exhibited therapeutic potential in solid tumors. Emerging data show that the function of blood vessels associated with tumors is critical in the response to these immunotherapies.

Full Text Link: Science Full Text

Reprint: Science Reprint

Effect of Aflibercept Plus Modified FOLFOX6 Induction Chemotherapy Before Standard Chemoradiotherapy and Surgery in Patients With High-Risk Rectal Adenocarcinoma: The GEMCAD 1402 Randomized Clinical Trial

What is the effect of an induction chemotherapy treatment with aflibercept plus a modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) followed by standard chemoradiotherapy and total mesorectal excision surgery in patients with magnetic resonance imaging–defined high-risk, locally advanced rectal adenocarcinoma?

Free article access: JAMA Oncology

Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges

J.D. Martin, G. Seano, R.K. Jain

Abnormal blood and lymphatic vessels create a hostile tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial fluid pressure. These abnormalities fuel tumor progression, immunosuppression, and treatment resistance. In 2001, we proposed a novel hypothesis that the judicious use of antiangiogenesis agents—originally developed to starve tumors—could transiently normalize tumor vessels and improve the outcome of anticancer drugs administered during the window of normalization. In addition to providing preclinical and clinical evidence in support of this hypothesis, we also revealed the underlying molecular mechanisms. In parallel, we demonstrated that desmoplasia could also impair vascular function by compressing vessels, and that normalizing the extracellular matrix could improve vascular function and treatment outcome in both preclinical and clinical settings. Here, we summarize the progress made in understanding and applying the normalization concept to cancer and outline opportunities and challenges ahead to improve patient outcomes using various normalizing strategies.

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Dual endothelin receptor inhibition enhances T-DM1 efficacy in brain metastases from HER2-positive breast cancer

Vasileios Askoxylakis, Gino B Ferraro, Mark Badeaux, David P Kodack, Isabelle Kirst, Ram C Shankaraiah, Christina S F Wong, Dan G Duda, Dai Fukumura, and Rakesh K Jain.

The effective treatment of cerebral metastases from HER2-positive breast cancer remains an unmet need. Recent studies indicate that activated astrocytes and brain endothelial cells exert chemoprotective effects on cancer cells through direct physical interaction. Here we report that the endothelin axis mediates protection of HER2-amplified brain metastatic breast cancers to the anti-HER2 antibody–drug conjugate ado-trastuzumab emtansine (T-DM1). Macitentan, a dual inhibitor of endothelin receptors A and B, improves the efficacy of T-DM1 against breast cancers grown in the brain. We show that direct contact of brain stroma with cancer cells is required for protection to T-DM1. Our data suggest that targeting the endothelin axis may be beneficial when anti-signaling agent and cytotoxic agent are combined. These findings may contribute to the development of therapeutic approaches with enhanced efficacy in the brain microenvironment..

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Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium

Giorgio Seano, Hadi T Nia, Kyrre E Emblem, Meenal Datta, Jun Ren, Shanmugarajan Krishnan, Jonas Kloepper, Marco C Pinho, William W Ho, Mitrajit Ghosh, Vasileios Askoxylakis, Gino B Ferraro, Lars Riedemann, Elizabeth R Gerstner, Tracy T Batchelor, Patrick Y Wen, Nancy U Lin, Alan J Grodzinsky, Dai Fukumura, Peigen Huang, James W Baish, Timothy P Padera, Lance L Munn, and Rakesh K Jain

The compression of brain tissue by a tumour mass is believed to be a major cause of the clinical symptoms seen in patients with brain cancer. However, the biological consequences of these physical stresses on brain tissue are unknown. Here, via imaging studies in patients and by using mouse models of human brain tumours, we show that a subgroup of primary and metastatic brain tumours, classified as nodular on the basis of their growth pattern, exert solid stress on the surrounding brain tissue, causing a decrease in local vascular perfusion as well as neuronal death and impaired function. We demonstrate a causal link between solid stress and neurological dysfunction by applying and removing cerebral compression, which respectively mimic the mechanics of tumour growth and of surgical resection. We also show that, in mice, treatment with lithium reduces solid-stress-induced neuronal death and improves motor coordination. Our findings indicate that brain-tumour-generated solid stress impairs neurological function in patients, and that lithium as a therapeutic intervention could counter these effects

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Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

Ioanna Keklikoglou, Chiara Cianciaruso, Esra Güç, Mario Leonardo Squadrito, Laura M Spring, Simon Tazzyman, Lore Lambein, Amanda Poissonnier, Gino B Ferraro, Caroline Baer, Antonino Cassará, Alan Guichard, M Luisa Iruela-Arispe, Claire E Lewis, Lisa M Coussens, Aditya Bardia, Rakesh K Jain, Jeffrey W Pollard, and Michele De Palma

Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the pro-metastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy./p>

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Quantifying solid stress and elastic energy from excised or in situ tumors. 

Nia HT, Datta M, Seano G, Huang, P, Munn LL, Jain RK.

Measuring Solid Stress

Solid stress, distinct from both tissue stiffness and fluid pressure, is a mechanical stress that is often elevated in both murine and human tumors. The importance of solid stress in tumor biology has been recognized in initial studies: solid stress promotes tumor progression and lowers the efficacy of anticancer therapies by compressing blood vessels and contributing to hypoxia. However, robust, reproducible, and objective methods that go beyond demonstration and bulk measurements have not yet been established. We have developed three new techniques to rigorously measure and map solid stress in both human and murine tumors that are able to account for heterogeneity in the tumor microenvironment.

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Methicillin-resistant Staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction

Dennis Jones, Eelco F. J. Meijer, Cedric Blatter, Shan Liao, Ethel R. Pereira, Echoe M. Bouta, Keehoon Jung, Shan Min Chin, Peigen Huang, Lance L. Munn, Benjamin J. Vakoc, Michael Otto, Timothy P. Padera

Lymphedema is associated with skin and soft tissue infections, and both can be recurring, causing continual suffering in affected patients. To better understand the relationship between bacterial infections and lymphedema, Jones et al. used intravital imaging to examine the lymphatics of mice infected with MRSA. They observed lymphatic muscle cell death, which led to prolonged dysfunction months after the bacteria had been cleared. In vitro experiments with human cells indicated that bacterial toxins were responsible for damaging the lymphatic muscle cells, suggesting that the toxins could be targeted in patients to interrupt this brutal cycle.



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Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

Joao Incio, Jennifer A. Ligibel, Daniel T. McManus, Priya Suboj, Keehoon Jung, Kosuke Kawaguchi, Matthias Pinter, Suboj Babykutty, Shan M. Chin, Trupti D. Vardam, Yuhui Huang, Nuh N. Rahbari, Sylvie Roberge, Dannie Wang, Igor L. Gomes-Santos, Stefan B. Puchner9, Christopher L. Schlett, Udo Hoffmman, Marek Ancukiewicz1, Sara M. Tolaney, Ian E. Krop, Dan G. Duda, Yves Boucher, Dai Fukumura, and Rakesh K. Jain

Tailored treatment for cancer in obesity

Antiangiogenic therapy with inhibitors of the vascular endothelial growth factor (VEGF) has not proven effective in patients with many tumor types, including breast cancer. Meanwhile, obesity is a well-known risk factor in many cancer types, and once again, this includes breast cancer. Now, Incio et al. link these two observations, having discovered a mechanism by which obesity promotes resistance to VEGF inhibitor therapy through increased interleukin-6 and possibly also fibroblast growth factor 2 in the tumor microenvironment. The authors target these pathways in mouse models of cancer with and without obesity and demonstrate that the deleterious effects of obesity on VEGF inhibition can be overcome through the appropriate combination therapy.



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Fatty acid synthesis is required for breast cancer brain metastasis

Ferraro, G.B., Ali, A., Luengo, A. et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat Cancer 2, 414–428 (2021).

Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2-positive breast cancer and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in the brain. We determine that this phenotype is an adaptation to decreased lipid availability in the brain relative to other tissues, resulting in site-specific depen- dency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase reduces human epidermal growth factor receptor 2-positive breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

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