Archive for the ‘News Article’ Category

 

Keith Flaherty, M.D.

Director of Clinical Research, Massachusetts General Hospital
Professor of Medicine, Harvard Medical School

 

Determinants of response and resistance to targeted therapies and immunotherapy in melanoma

 
Significant therapeutic advances have been made in advanced melanoma over the past decade. For almost half of melanoma patients, BRAF inhibitor-based therapy has provided a reliable disease-controlling therapy in the metastatic setting and curative effect in the adjuvant setting. For those same patients and the remaining population of melanoma patients whose tumor lack a BRAF mutation, immune checkpoint antibody therapy has produced a benefit that was first documented in melanoma prior to extending to 14 additional cancer types. Ongoing research continues to focus on resistance to both therapeutic types in model systems and in patients’ tumors. An emerging theme has been the elucidation of a epigenetic state change that associates with resistance to both BRAF inhibitor and immune checkpoint antibody-based therapy. This evidence and emerging evidence supporting therapeutic approaches that might undercut the determinants of resistance will be discussed.
 

10:00 am – 11:00 am
Thursday, May 16, 2019

Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, Room 563
Boston, MA 02115

Hosted by Luca Gerosa, Ph.D.

Posted in News Article | Comments Off on HiTS Seminar: Keith Flaherty, MD, 10:00 am, Thursday, May 16, 2019

 

Christine Leslie, Ph.D.

Associate Member, Computational Biology Program
Sloan Kettering Institute

 

Decoding Epigenetic States of Immune and Cancer Cells

 
Dysregulated epigenetic programs are a feature of many cancers, and the diverse differentiation states of immune cells as well as their dysfunctional states in tumors are in part epigenetically encoded.  We will present recent analysis work and computational methodologies from our lab to decode epigenetic programs from genome-wide data sets. In a recent collaborative work, we characterized chromatin states governing CD8 T cell dysfunction in cancer and reported that tumor-specific T cells differentiate to dysfunction through two discrete chromatin states: an initial plastic state that can be functionally rescued (i.e. through immunotherapy) and a later fixed state that is resistant to therapeutic reprogramming.  We now follow up on this work by presenting a computational framework to decipher transcriptional programs governing chromatin accessibility and gene expression in normal and dysfunctional T cell responses through a large-scale analysis of published data from mouse tumor and chronic viral infection models.  This modeling shows that in all these systems, T cells commit to becoming dysfunctional early after an immune challenge, rather than first mounting and then losing an effector response.  Through scRNA-seq analysis, we characterize the phenotypic diversity of this common trajectory from plastic to fixed dysfunction.  We will also present a recent collaboration with the Sawyers lab on FOXA1 mutants in prostate cancer, showing that somatic alterations in this pioneer transcription factor lead to altered differentiation programs, through analysis of ATAC-seq in mouse prostate organoid systems.  Finally, we will describe a novel machine learning approach called BindSpace to leverage massive in vitro TF binding data from SELEX-seq experiments through a joint embedding of DNA k-mers and TF labels, leading to improved prediction of TF binding.
 

10:00 am – 11:00 am
Thursday, May 2, 2019

Harvard Medical School
210 Longwood Avenue
Goldenson Bldg, Room 122
Boston, MA 02115

Hosted by Artem Sokolov, Ph.D.

Posted in News Article | Comments Off on HiTS Seminar: Christina Leslie, 10:00 am, Thursday, May 2, 2019

American Society for Biochemistry and Molecular Biology

Scientists at Harvard Medical School and the Dana-Farber Cancer Institute have developed a method that exploits the multitargeted nature of a chemical inhibitor to pinpoint vulnerabilities within cancer cells.

When signaling pathways within cells are triggered, proteins activate through a chain reaction, like a row of tumbling dominoes, until the final protein influences some cellular function. In some tumors, multiple signaling pathways drive cell growth and survival. This redundancy means that if one pathway ceases activity, another could continue driving cancerous behavior. Thus, drugs with the ability to shutdown multiple pathways at the same time could be advantageous.

Many cancer drugs, including some clinically approved kinase inhibitors, were originally designed to block the function of specific molecules but it is now known that their benefits might not always stem from the inhibition of single targets.

“Many of these covalent inhibitors are in fact some degree polypharmacological in their action and they can target multiple things,” said Nathanael Gray, a professor of biological chemistry and molecular pharmacology at Harvard Medical School and the Dana Farber Cancer Institute in Boston, Massachusetts. “They’re advertised as working through one target, but people in the field know that several other targets contribute.”

In a study published in the Journal of Biological Chemistry, a team researchers led by Gray identified key molecules that support the survival of a specific type of lung cancer cells. By analyzing the response of these cells to a cancer-killing kinase inhibitor with numerous targets, they were able to show that the anticancer effects were likely elicited by simultaneous inhibition of specific molecules in two signaling pathways. This approach to drug-target discovery could be useful for designing drugs that selectively attack multiple proteins, which is beneficial for managing certain tumors.

Although kinase inhibitors hit multiple targets, most were not designed to do so, which means they might bind to molecules unnecessarily and lead to adverse effects. And because it has been unclear which combinations of targets would have the most desirable effects, it has been challenging for researchers to purposefully design multitargeted drugs for cancer, Gray said.

To allow better drug design, Gray sought to discover which of the many buttons pushed by these inhibitors enables their anticancer effects. In a study to be published later this year, Gray and his lab investigated the kinase inhibitor SM1-71 and, using a suite of chemical proteomic and cellular techniques, showed that it actually binds to dozens of kinases, some of which are involved in critical signaling pathways that support cell survival and growth.

“It was sort of like a stick of dynamite and really could hit a lot of different targets,” Gray said.

In the study published in JBC, the researchers exposed different types of cancer cells to SM1-71 and found that the drug was highly toxic to a specific line of lung cancer cells with mutated KRAS protein, which is common in some tumors and leads to constant activation of signaling pathways that drive cell growth. The ability of the inhibitor to kill these cells in spite of this mutation suggested that targets in several pathways were being hit, Gray said.

To find which inhibitory interactions were curbing cancer activity, the researchers first identified which kinases in their previously generated list of SM1-71 targets were known to be key signaling proteins for cell growth and survival. They then narrowed down these candidates with Western blotting, which showed if any of these proteins from the cancer cells were actually being inhibited, and saw that proteins in two critical pathways were indeed being blocked.

The authors then applied various kinase inhibitors used in research and the clinic to see if specifically inhibiting any combination of these proteins would replicate the effects that SM1-71 had on the cancer cells. In the end, inhibiting MEK1/2 and IGF1R/INSR proteins at the same time demonstrated similar effects, suggesting these are crucial targets in this lung cancer line, Gray said.

SM1-71 itself would not likely be viable in humans because it binds to too many proteins and can lead to collateral damage, Gray said. But uncovering its most important targets within specific pathways could aid the design of future drugs that can shutdown multiple signaling pathways in tumors.

“The next step would be to try to preserve the efficacy driving targets while getting rid of targets that may be contributing to the toxicology,” Gray said.

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DOI: 10.1074/jbc.RA118.006805

This work was supported by National Institutes of Health Grants P50GM107618, U54-CA225088, and U54-HL127365; a Jonathan M. Goldstein and Kaia Miller Goldstein systems pharmacology fellowship; and a Linde Family gift.

Other authors on this study include Suman Rao, Guangyan Du, Marc Hafner, Kartik Subramanian and Peter K. Sorger.

American Society for Biochemistry and Molecular Biology Article: https://www.eurekalert.org/pub_releases/2019-04/asfb-uap040419.php

Journal of Biological Chemistry Paper: http://www.jbc.org/content/early/2019/03/11/jbc.RA118.006805

About the Journal of Biological Chemistry

JBC is a weekly peer-reviewed scientific journal that publishes research “motivated by biology, enabled by chemistry” across all areas of biochemistry and molecular biology. The read the latest research in JBC, visit http://www.jbc.org/.

About the American Society for Biochemistry and Molecular Biology

The ASBMB is a nonprofit scientific and educational organization with more than 11,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in government laboratories, at nonprofit research institutions and in industry. The Society publishes three journals: the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics. For more information about ASBMB, visit http://www.asbmb.org.

Posted in News Article, Press Release | Comments Off on Using a Promiscuous Inhibitor to Uncover Cancer Drug Targets

 

Matthew Vander Heiden, M.D., Ph.D.

Associate Professor of Biology and Associate Director
The Koch Institute of Integrative Cancer Research at MIT

 

Metabolic Constraints of Cell Proliferation

 
Complex regulatory mechanisms enable cell metabolism to match physiological state. The major pathways cells use to turn nutrients into energy and to synthesize macromolecules have been elucidated; however, there remain many unanswered questions regarding how metabolism supports cell proliferation and thus how best to target metabolism for cancer treatment. We have found that the redox state of the cell determines whether cells can produce oxidized biomass and support cell proliferation. We also find that both cell intrinsic and cell extrinsic factors can influence which nutrients are limiting for proliferation in different contexts. This explains some cancer metabolism phenotypes such as the Warburg effect, and suggests how different cancers can be differentially sensitive to inhibition of specific metabolic enzymes. How cell intrinsic factors cooperate with extrinsic metabolic inputs to influence tumor progression will be discussed in the context of how best to exploit altered metabolism to treat cancer.
 

10:00 am – 11:00 am
Thursday, April 18, 2019

Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, 5th Floor, Room 563
Boston, MA 02115

Hosted by Chris Chidley, Ph.D.

Posted in News Article | Comments Off on HiTS Seminar: Matthew Vander Heiden, 10:00 am, Thursday, April 18, 2019

 

Elias Bareinboim, Ph.D.

Purdue University

 

Causal Inference and Fusion

 
Causal inference is usually dichotomized into two categories, experimental (Fisher, Cox, Cochran) and observational (Neyman, Rubin, Robins, Dawid, Pearl) which, by and large, are studied separately. Understanding reality is more demanding. Experimental and observational studies are but two extremes of a rich spectrum of research designs that generate the bulk of the data available in practical, large-scale situations. In typical medical explorations, for example, data from multiple observations and experiments are collected, coming from distinct experimental setups, different sampling conditions, and heterogeneous populations.

In this talk, I will introduce the data-fusion problem, which is concerned with piecing together multiple datasets collected under heterogeneous conditions (to be defined) so as to obtain valid answers to queries of interest. The availability of multiple heterogeneous datasets presents new opportunities to causal analysts since the knowledge that can be acquired from combined data would not be possible from any individual source alone. However, the biases that emerge in heterogeneous environments require new analytical tools. Some of these biases, including confounding, sampling selection, and cross-population biases, have been addressed in isolation, largely in restricted parametric models. I will present my work on a general, non-parametric framework for handling these biases and, ultimately, a theoretical solution to the problem of fusion in causal inference tasks.

Suggested readings:
E. Bareinboim and J. Pearl, Causal inference and the Data-Fusion Problem, Proceedings of the National Academy of Sciences, 113(27): 7345-7352, 2016. https://www.pnas.org/content/113/27/7345
 

10:00 am – 11:00 am
Thursday, March 21, 2019

Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, 5th Floor, Room 563
Boston, MA 02115

Hosted by John Bachman, Ph.D.

Posted in News Article | Comments Off on HiTS Seminar: Elias Bareinboim, 10:00 am, Thursday, March 21, 2019

 

David Feldman

Broad Institute, Cambridge, MA

 

Scalable Image-based Genetic Screens

 
Genetic screens (e.g., CRISPR loss-of-function, ORF gain-of-function) provide a powerful means to identify genes underlying cellular processes. A wide range of cell behaviors can be observed by imaging assays, including dynamic responses from the scale of minutes to generations. However, image-based screens have been difficult to scale due to the requirement to test each perturbation one at a time. We developed a pooled approach for image-based genetic screens in mammalian cells, using in situ sequencing to sequence the perturbation (e.g., CRISPR sgRNA) directly in fixed cells. We piloted the method by imaging live-cell NF-kB translocation kinetics in a collection of ~1,000 gene knockouts and are now moving to genome-scale. We hope that this approach, which requires no special hardware beyond an automated widefield microscope, will enable widespread use of highly multiplexed image-based screens.
 

10:00 am – 11:00 am
Thursday, January 17, 2019

Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, 5th Floor, Room 563
Boston, MA 02115

Hosted by Michael Tsabar, Ph.D.

Posted in News Article | Comments Off on HiTS Seminar: David Feldman, 10:00 am, Thursday, January 17, 2019

 

Luke Lee, Ph.D.

University of California, Berkeley

 

Ultrafast Photonic PCR and Organoids on Chip

 

10:00 am – 11:00 am
Tuesday, November 20, 2018

Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, 5th Floor, Room 563
Boston, MA 02115

Hosted by Peter Sorger, Ph.D.

Posted in News Article | Comments Off on HiTS Seminar: Luke Lee, PhD, 10:00 am, Tuesday, November 20, 2018

 

Nathanael Gray, Ph.D.

Dana-Farber Cancer Institute

 

Targeted Protein Degradation as a
New Drug Development Strategy

 

10:00 am – 11:00 am
Thursday, October 11, 2018

Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, 5th Floor, Room 563
Boston, MA 02115

Hosted by Kenichi Shimada, Ph.D.

Posted in News Article | Comments Off on HiTS Seminar: Nathanael Gray, PhD, 10:00 am, Thursday, October 11, 2018

 

Dave Mellert, Ph.D.

The Jackson Laboratory

 

Data Management for Data Science at The Jackson Laboratory

Research data are usually collected with a specific question in mind and are thus most often managed and stored in a manner that makes reuse difficult or impossible. At the same time, the world is seeing an explosion of new statistical and computational methodologies that can extract meaning from extremely large datasets. The Jackson Laboratory (JAX) aims to fully leverage these advances by improving our stewardship of research data—our goal is to make our data FAIR (Findable, Accessible, Interoperable, and Reusable). By incorporating our diverse research data into a FAIR-compliant management framework, we will create new opportunities for data scientists to apply data-mining and machine-learning algorithms to our rich data resources. In this presentation, I will discuss JAX’s overall vision of Data Management for Data Science, describe our plans for implementation and progress, and present specific use-cases for how we expect researchers to interact with our data in the future.

 

10:00 am – 11:00 am
Thursday, September 20, 2018

Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, 5th Floor, Room 563
Boston, MA 02115

Hosted by Douglas Russell

Posted in News Article | Comments Off on HiTS Seminar: Dave Mellert, PhD, 10:00 am, Thursday, September 20, 2018

Ben Gyori named 2018 DARPA Riser

Benjamin M. Gyori, Ph.D., A Research Scientist in Therapeutic Science was selected as one of 50 DARPA Risers: up and coming early career investigators with the potential to perform innovative research at the frontiers of science and technology relevant to the mission of DARPA.

As a DARPA Riser, Ben will attend DARPA’s 60th Anniversary Symposium (D60) at Gaylord National Harbor, Sept 5-7, and present his proposal on a computer system which autonomously monitors events and scientific discoveries, integrates them into actionable models, and proactively reports relevant analysis results.

D60 will bring together 1,500 forward-thinking scientists, engineers, and other innovators interested in sharing ideas and learning how DARPA has shaped and continues to shape breakthrough technologies. D60 will also feature Dr. Peter Sorger, who leads the Harvard Program in Therapeutic Science, as an invited speaker on the Accelerating Science panel where he will present on AI technologies for bridging mathematical models and cellular biology.

Ben’s current work focuses on computational approaches to accelerate scientific discovery. He has been an active performer in the DARPA Big Mechanism, Communicating with Computers, World Modelers, and Automated Scientific Discovery Framework programs.

Gyori is a co-developer of INDRA, a system which automatically assembles information about biochemical mechanisms extracted from the scientific literature into explanatory and predictive models. He is also leading the development a collaborative dialogue system allowing a human user to talk with a machine partner to learn about molecular mechanisms, and formulate, and test model hypotheses.

 

 

 

 

 

 

 

 

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