Rakesh Jain, Ph.D.

Abstract: Mathematical modelling has proven to be a valuable tool in predicting the delivery and efficacy of molecular, antibody-based, nano and cellular therapy in solid tumours. Mathematical models based on our understanding of the biological processes at subcellular, cellular and tissue level are known as mechanistic models that, in turn, are divided into continuous and discrete models. Continuous models are further divided into lumped parameter models — for describing the temporal distribution of medicine in tumours and normal organs — and distributed parameter models — for studying the spatiotemporal distribution of therapy in tumours. Discrete models capture interactions at the cellular and subcellular levels. Collectively, these models are useful for optimizing the delivery and efficacy of molecular, nanoscale and cellular therapy in tumours by incorporating the biological characteristics of tumours, the physicochemical properties of drugs, the interactions among drugs, cancer cells and various components of the tumour microenvironment, and for enabling patient-specific predictions when combined with medical imaging. Artificial intelligence-based methods, such as machine learning, have ushered in a new era in oncology. These data-driven approaches complement mechanistic models and have immense potential for improving cancer detection, treatment and drug discovery. Here we review these diverse approaches and suggest ways to combine mechanistic and artificial intelligence-based models to further improve patient treatment outcomes… Continue reading.

Rakesh Jain PhD, Director of the E.L. Steele Laboratories for Tumor Biology at Massachusetts General Hospital and A. Werk Cook Professor of Radiation Oncology at Harvard Medical School, is senior author of a new study in PNAS, Targeting EPHB2/ABL1 Restores Anti-Tumor Immunity in Preclinical Models of Ependymoma.

How would you summarize your study for a lay audience?

Ependymoma (EPN) is a common form of brain cancer in children, with few available therapies that have limited efficacy.

Despite the advances in understanding the biology of EPN, managing patients with different stages of EPN remains challenging. Surgical resection and radiation therapy are the standard treatments for EPN. However, not all EPNs can be safely resected, especially those that develop intracranially, and irradiation may cause long-term toxicities… Continue reading.

The National Foundation for Cancer Research (NFCR) announced today that Rakesh K. Jain, Ph.D., has been selected to receive the 2022 Szent-Györgyi Prize for Progress in Cancer Research. The blue-ribbon Prize selection committee, consisting of renowned leaders in cancer research, elected Dr. Jain for his pioneering research and breakthrough discoveries on overcoming barriers posed by the tumor microenvironment (TME) which led to the improved delivery and efficacy of anti-cancer medicines. His groundbreaking and innovative research has fundamentally transformed the understanding of tumor biology and directly informed the development and approval of new drug-combinations to treat cancer patients.

Rakesh K. Jain, Ph.D., will be honored at the Szent-Györgyi Prize award ceremony on October 22, 2022, at The National Press Club in Washington, D.C… Continue reading.

In this large retrospective study, patients with hypertension who were concomitantly taking a RAAS inhibitor during ICI therapy had better overall survival. This benefit was primarily noted among patients with gastrointestinal and genitourinary cancers. Prospective randomized trials are warranted to further evaluate and specify the benefit of RAAS inhibitors in patients with cancer who receive ICI therapy… Continue reading.

We demonstrate that modelling of COVID-19 pathobiology can suggest biomarkers that predict optimal response to a given immunomodulatory treatment. Mathematical modelling thus constitutes a novel adjunct to predictive enrichment and may aid in the reduction of heterogeneity in critical care trials… Continue reading.

A mathematical model revealed that the optimal time to initiate immune-modulating therapy in COVID-19 differed according to patients’ medical history and risk factors. Different patients also required different types of immunomodulation for optimal therapy.

Certain biological markers that differed based on patient characteristics determined optimal treatment initiation time, and these markers pointed to particular biologic programs or mechanisms that affected a patient’s outcome.

Use of the model may help physicians tailor treatments to different patients and also indicate which patients are most likely to respond to certain drugs tested in clinical trials… Continue reading.

For many individuals with different types of cancer, immune checkpoint inhibitors can effectively boost their immune system to fight their disease, but not all patients benefit from these medications. Now a team led by investigators at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) has developed an approach to help identify potential clinical markers that may indicate which patients will respond to immune checkpoint inhibitors and which should be treated with other strategies. The findings are published in the Proceedings of the National Academy of Sciences.

For the study, the scientists developed an approach whereby they implanted breast cancer tumors into mice and then treated the animals with immune checkpoint inhibitors. “We first developed a resection and response bilateral tumor model in which we put one breast tumor in each side of the mouse breast. We then remove one tumor to evaluate the tumor microenvironment and we monitor the response of the other, non-resected, tumor to immune checkpoint blockade, identifying the mouse as a responder or a non-responder,” explained lead author Ivy X. Chen, PhD, a former postdoctoral fellow at MGH’s E.L. Steele Laboratories for Tumor Biology. Using this model system, the researchers found that the responding tumors contained higher numbers of cancer-killing “cytotoxic” T immune cells and fewer numbers of certain immune suppressor cells early after the start of treatment… Continue reading.

Scientists working at the intersection of math and medicine propose new strategies based on mathematical modeling and known molecular mechanisms to improve the efficacy of lifesaving immunotherapies for cancerous tumors. The work was published on February 3 in the Proceedings of the National Academy of Sciences.

Cancer cells can evade immune responses by activating negative regulatory pathways, known as immune checkpoints, that block T-cell activation. Inhibition is mediated by binding of programmed cell death protein 1 (PD-1) receptor of T cells to the ligand (PD-L1) or binding of cytotoxic T lymphocyte antigen 4 (CTLA-4) receptor of T cells to the B7 molecules in response to various cytokines, such as interferon-γ (IFNγ)… Continue reading.

Immune checkpoint inhibitors are important medications that boost the immune system’s response against certain cancers; however, they tend to be ineffective against glioblastoma, the most deadly primary brain tumor in adults. New research in mice led by investigators at Massachusetts General Hospital (MGH) and the University of Florida reveals a promising strategy that makes glioblastoma susceptible to these medications. The findings, which are published in the Proceedings of the National Academy of Sciences, indicate that such combination therapy should be tested in clinical trials of patients with glioblastoma, for whom there is no known cure.

Part of the reason glioblastoma does not respond well to immune checkpoint inhibitors and other immunotherapies is because cells called myeloid-derived suppressor cells (MDSCs) infiltrate the region surrounding glioblastoma tumors, where they contribute to immunosuppression, tumor progression, and treatment resistance. Thus, targeting these cells may augment immunotherapy and improve responses to treatment in affected patients… Continue reading.

Edwin L. Steele Laboratories, Harvard – September 16 – 18, 2019

This course, directed by Dr. Rakesh K. Jain, will take place from September 16 – 19, 2019, at the Massachusetts General Hospital East, CNY-149, Boston, Massachusetts and offer the best in critical analysis of what is currently known about the tumor microenvironment, angiogenesis, metastasis, immunology, targeted therapies, metabolism and a newly introduced topics: the Microbiome and Circadian clock and Tumor Metabolic Vulnerabilities. Learn more and register here .

For any further questions, please contact Ms. Elizabeth Garzon EGARZON@mgh.harvard.edu.

New research has revealed a correlation between fibrosis, CXCR4 expression, and immunosuppression in metastatic breast cancer, according to a study published in PNAS. The findings could lead to new therapeutic approaches that could improve the efficacy of immunotherapy in patients with the disease.

According to the study, many treatment-resistant tumors are highly fibrotic. Fibrosis, which is the overgrowth of connective tissue, can inhibit the efficacy of immunotherapies against breast cancer. The researchers suggested that drugs targeting fibrosis may help improve the response to immunotherapy in these patients.

The study provided insight into understanding how the physical features of tumors can block the response to cancer therapies and identified the role of the CXCR4 signaling pathway in resistance to immunotherapies. In an examination of paired biopsies of primary and metastatic breast tumors from the same patients, the researchers found that CXCR4 expression was linked to high levels of fibrosis and expression of immunosuppressive proteins in all subtypes of breast cancer… Continue reading.

A study led by investigators from Massachusetts General Hospital (MGH) and the University of Cyprus reveals details of a way the dangerous brain tumors called glioblastomas resist the effects of antiangiogenic drugs designed to cut off their blood supply. In their report published in PNAS, the researchers describe how the tumors can spread along existing blood vessels in normal tissue, a process called vessel co-option that can lead to compression of those vessels, reducing the oxygen supply to adjacent tissues and actually stimulating angiogenesis.

“The treatments designed to starve tumors by pruning away blood vessels have provided little or no survival benefits to patients with glioblastoma, says Rakesh K. Jain, PhD, director of the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology and senior author of the PNAS report. “Because of its ability to circumvent a tumor’s need to develop a new blood supply, vessel co-option can confer resistance to antiangiogenic therapy. Unfortunately this mode of tumor progression is difficult to target because the underlying mechanisms are not fully understood… Continue reading.

A new study from a Massachusetts General Hospital (MGH) research team has found that the hypertension drug losartan, which targets the angiotensin signaling pathway, may improve the effectiveness of chemotherapy agents used to treat ovarian cancer. Previous research from the same team identified a similar effect for losartan in animal models of breast and pancreatic cancer, leading to a phase 2 clinical trial that had promising results against pancreatic cancer.

“We know that solid stress imposed by growing cancer cells and the extracellular matrix molecules they produce can compress blood vessels, reducing delivery of drugs and oxygen to tumors,” says Lei Xu, PhD, of the Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology, co-senior author of the report published online in PNAS. “The extracellular matrix itself can keep high-molecular-weight drugs from penetrating tumors, and angiotensin signaling contributes to matrix formation. Since levels of an important enzyme in the angiotensin pathway are elevated and associated with poor outcomes in ovarian cancer, we investigated whether use of losartan to decrease fibrosis could improve outcomes in animal models of ovarian cancer… Continue reading.

A Massachusetts General Hospital (MGH)-led research team has demonstrated, for the first time, how solid stress – the physical forces exerted by the solid components of a tumor – impacts the tissue surrounding brain tumors and contributes to resulting neurological dysfunction and neuronal cell death. In their report published in Nature Biomedical Engineering, the investigators identify characteristics of tumors most likely to impose solid stress, describe a potential way of distinguishing patients with such tumors, and identify the neuroprotective drug lithium as a promising treatment strategy.

“The mechanical abnormalities of cancer affect tissue and biology through multiple mechanisms,” says Rakesh K. Jain, PhD, director of the Steele Laboratories of Tumor Biology in the MGH Radiation Oncology Department, senior and corresponding author of the report. “Over the last decade, our team has identified and characterized solid stress as a new biomechanical abnormality in tumors, but little has been known about how these forces affect tissues surrounding a brain tumor, potentially impairing neurological function… Continue reading.

Abstract

Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer… Continue reading.

A study led by a team of Massachusetts General Hospital (MGH) investigators has analyzed, for the first time, the mechanisms underlying the use of focused ultrasound to improve the delivery of anti-cancer drugs across the blood brain barrier into brain tumors. Their report published in PNAS uses advanced microcopy techniques and mathematical modeling to track the potential of this promising, minimally invasive treatment approach in an animal model of breast cancer brain metastasis. The team also included investigators from Georgia Institute of Technology, the University of Edinburgh and Brigham and Women’s Hospital.

…

“By explaining and underscoring the potential of combining focused ultrasound with different drugs for the treatment of brain metastases, our findings provide important scientific principles for the optimal clinical use of the technology,” says senior author Rakesh Jain, PhD, director of the Steele Labs for Tumor Biology and the Cook Professor of Radiation Oncology at Harvard Medical School. “In particular, they may allow identification of specific administration protocols for improved drug uptake – such as slow infusion rather than bolus administration – and support the hypothesis that the approach needs to be tested individually for different drugs. By laying the groundwork for more rational design and deeper understanding of focused-ultrasound-based treatment, our work could help improve treatment of any brain tumor – primary or metastatic – and could also revolutionize approaches to immunotherapy of tumors by improving localized delivery of tumor-killing immune cells… Continue reading.

As a research facility at one of America’s top hospitals buzzes with activity, two men chat in a narrow, unassuming office. One is jaunty, with a smile as his default facial expression and a melodic lilt to his voice. The other is more reserved and speaks with a softer, deeper tone.

They haven’t seen each other in about a year and a half, but once they’ve shaken hands, their conversation immediately turns to science. When your work has the potential to save millions of lives, that’s what you do.

Rakesh K. Jain, COE74M, 76PhD, has spent decades working on some of the world’s most pressing health problems, and has come to be regarded as one of America’s most accomplished scientists. Arup K. Chakraborty, COE88PhD, is tackling one of the world’s most elusive challenges: creating a vaccine for the human immunodeficiency virus (HIV), the causative agent of AIDS.

Both professors are where they are today partly thanks to the school that helped set their scholarly paths: the University of Delaware… Continue reading.

A multi-institutional research team has identified a new mechanism by which the dangerous brain tumors called gliomas develop resistance to anti-angiogenic treatment. The team’s report, published online in Cancer Cell, describes finding how different molecular subtypes of glioma cells use different strategies to spread through the brain and how anti-angiogenic treatment selects for a treatment-resistant cellular subtype.

“Despite massive basic and clinical research efforts, the treatment of glioblastoma and other malignant gliomas remains one of the most challenging tasks in clinical oncology,” says Rakesh Jain, PhD, director of the Edwin L. Steele Laboratories for Tumor Biology in the Massachusetts General Hospital (MGH) Department of Radiation Oncology and co-senior author of the report. “Glioblastomas are highly vascularized and interact closely with pre-existing blood vessels for oxygen and nutrients. They also contain a very diverse population of cells, with characteristics of stem cell and other cells found within the brain, and may use different strategies to recruit or access blood vessels, depending on the local microenvironment and on treatments that are applied… Continue reading.

Obesity – which is already known to reduce survival in several types of cancer – may explain the ineffectiveness of angiogenesis inhibitors in the treatment of breast cancer. A research team led by Massachusetts General Hospital (MGH) investigators describes finding, for the first time, that obesity and obesity-related molecular factors appear to induce resistance to antiangiogenic therapy in breast cancer patients and in two mouse models of the disease. Their report in Science Translational Medicine also details specific obesity-related factors underlying that resistance and outlines potential therapeutic strategies that may overcome it.

“Collectively, our clinical and preclinical results indicate that obesity fuels resistance to anti-vascular endothelial growth factor therapy in breast cancer via production of several inflammatory and pro-angiogenic factors, depending on the subtype of cancer,” says Joao Incio, MD, PhD, of the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology, lead author of the report. “Targeting these resistance factors may rejuvenate the use of antiangiogenic therapy in breast cancer treatment.”

……

Rakesh K. Jain, PhD, director of the Steele Labs in the MGH Department of Radiation Oncology, is co-senior author of the Science Translational Medicine report. Jain is the Cook Professor of Radiation Oncology (Tumor Biology), and Fukumura is an associate professor of Radiation Oncology at Harvard Medical School. Support for the study includes Department of Defense Breast Cancer Research Innovator Award W81XWH-10-1-0016; National Cancer Institute grants R01-CA126642, R35CA197743, P01-CA080124, R01-CA208205, R01-CA096915 and S10-RR027070; and grants from the Harvard Ludwig Cancer Center and the National Foundation for Cancer Research… Continue reading.

The addition of an immunotherapy may prevent serious hearing damage related to radiotherapy that treats tumors associated with neurofibromatosis 2 (NF2), according to a study published by PNAS Plus.

The researchers found that crizotinib inhibited a molecular pathway that improved the radiosensitivity of tumors in mice models of the genetic disease, which lead to a reduced dose. The treatment also was observed to stop the growth of cultured cancer cells from patients with NF2.

Additionally, the authors developed a new mouse model that better mimics NF2 hearing loss and a system for culturing NF2 tumor cells.

“The hallmark of NF2 are intracranial tumors called vestibular schwannomas, which typically lead to profound hearing loss,” said co-corresponding author Lei Xu, MD, PhD. “For most patients, hearing loss is the most disabling symptom of these tumors, and the primary treatments for growing tumors—surgery and radiation therapy—can further damage hearing. The development of a novel therapeutic strategy with enhanced efficacy and minimal treatment-related hearing loss is urgently needed… Continue reading.

WASHINGTON, DC: This year’s National Medal of Science winner Rakesh K. Jain said he was thrilled to receive the prestigious award from President Barack Obama.

“It’s an absolute thrill to receive this from President Obama,” he remarked from a general press podium outside of the White House just moments after the award ceremony. “He is really one of my heroes.”

Jain, a professor at Harvard Medical School and Massachusetts General Hospital, was one of the 17 individuals who received the National Medal of Science and the National Medal of Technology and Innovation from Obama at the White House on May 19.

Jain also offered a poignant nugget of advice to any young Indian Americans who find themselves drawn to STEM fields.

“Follow your passion,” he said. “Do what your heart and mind what you to and work hard. If you work hard and you’re passionate about something, you’re going to get there. That’s my thinking.”