Sheila Singh

Last updated
Sheila Singh
CitizenshipCanadian
Alma mater
Children2
Scientific career
FieldsNeurobiology, Molecular Genetics, Surgery, Cancer Stem Cell Biology, Biochemistry
Institutions
Website http://sheilasinghlab.ca/

Sheila K. Singh MD, PhD, FRCSC [1] is a chief pediatric neurosurgeon at McMaster Children's Hospital in Ontario, Canada. [1] She is also Professor of Surgery and Biochemistry, the Division Head of Neurosurgery at Hamilton Health Sciences, the Research Director for McMaster's Division of Neurosurgery, and a scientist/principal investigator appointed to the Stem Cell and Cancer Research Institute at McMaster University. [1] [2]

Contents

She holds a Tier 1/ Senior Canada Research Chair in Human Brain Cancer Stem Cell Biology, and is Director of the McMaster Surgeon Scientist Program (SSP), which is a part of McMaster's pre-established Clinical Investigator Program (CIP) that provides research training for surgical residents. [1] [3]

Education

Singh graduated from McGill University in 1994 with a bachelor's degree in neurobiology and molecular genetics, and from McMaster University with an MD in 1997. She subsequently trained in neurosurgery at the University of Toronto from 1997-2007 and completed a PhD in the Surgeon Scientist Program (SSP) at McMaster University. [2] In 2006, Singh became certified in neurosurgery by The Royal College of Physicians and Surgeons of Canada (RCPSC) and then did a fellowship in pediatric neurosurgery at SickKids from 2006-2007. [2]

She has been recognized by invitations to serve as a grant reviewer for the NIH and CIHR. She has served as a brain tumor expert reviewer for the Pediatric Provincial Oncology Plan and the Pediatric Oncology Group of Ontario. She was a member of the Stem Cell Network AGM Steering Committee of the 2012 Till and McCulloch Meeting. She is active in the European Society for Medical Oncology and is on the editorial boards of Acta Neuropathologica Communications and of Current Pathobiology Reports. She is also a scientific advisor to Arch Biopartners of Toronto.

In 2017, she was named to the Royal Society of Canada's College of New Scholars, Artists, and Scientists. [4] In 2017, she was also made a University Scholar by the President of McMaster University. [2]

While in medical school, Singh encountered two five-year-old boys with brain tumors, both named Christopher. They were treated with the best current therapies of the time, however one flourished and the other died. This left her questioning the outcome, sparking her interest in cancer research. [1]

Research lab

The Sheila Singh Lab research program consists of a team of around 20 undergraduate, graduate and postdoctoral students with Singh as the principal investigator (PI) working at the Stem Cell and Cancer Research Institute in Hamilton. [1] [2] Sheila is the first woman to lead such a program as PI and the first scientist from McMaster to do so. [2]

Singh discovered an abnormal stem cell, the brain tumor initiating cell (BTIC), which may be the key to understanding the formation of brain tumors. [1]

The driving idea in Singh's research is the idea that only a small population of cancer stem cells in a brain tumor are capable of propagating, thus focusing on the rare tumor stem cell and not every cell in the tumor. So Singh's lab focuses on therapies that target the BTIC in hopes that it could better halt the propagation of tumors. Singh's lab focuses on understanding the molecular mechanisms that govern BTIC self-renewal, building upon cell culture techniques used for isolating normal neural stem cells (NSC), applying them to brain tumors and developing a xenograft model to study BTIC activity. [1]

Singh's lab currently studies the regulation of BTIC signaling pathways in medulloblastomas (MB), glioblastomas (GBM), and brain metastases (BM). [1] Singh's lab found that patients that have a higher proportion of BTICs may have shorter survival and a worse prognosis, offering insight into patient prognosis and forming the basis for medical therapies aimed at the BTIC. [1]

On her inspiration for her research, Singh said, "You see a lot of things in pediatric neurosurgery and all of them — good and bad — inspire my research. And every person who works with me has a direct connection to the ‘Why?’ of research. Very often patients and their families will come for a tour of the lab and my people get to meet them. There is a real connection. People in my lab work twice as hard because they have that direct motivation. I began my research career inspired to understand why one brain tumor patient with flourished, while the other with the same disease died. Now, my research program is dedicated to applying a developmental neurobiology approach to the study of human brain tumors. We do this by developing pre-clinical models that recapitulate the human disease. Our ultimate goal is to generate novel, targeted and effective therapies for brain tumor patients." [1]

Medulloblastoma

Singh's lab found that the poor patient survival associated with medulloblastomas correlates with the increased presence of BTICs. Singh's lab aims to study genes that regulate stem cell signaling pathways in MB patients in order to provide specific and individualized therapies that target BTIC. [1]  

Current projects [1]

  • Identify druggable targets that work in combination with Bmi1 inhibition to decrease MB progression and spinal dissemination in our therapy adapted patient-derived xenograft (PDX) model of MB recurrence.
  • Describe the role of BPIFB4 as a potent regulator of self-renewal and specific driver of MB relapse.
  • Identification of potent chemical compounds that specifically target recurrent MB spinal metastases.
  • Elucidate the role of the RNA-binding proteins Msi1 and Msi2 in recurrent MB.
  • Determine whether activation of Wnt signaling can decrease MB stem cell self- renewal and tumor progression in our MB patient-derived xenograft (PDX) model.

Glioblastoma

Singh's lab found that the poor patient survival associated with glioblastomas correlates with the increased frequency of BTICs along with the high degree of intratumoral heterogeneity, which affect the development of treatment in GBM. Singh's lab aims "to identify new therapeutic targets that drive clonal evolution in treatment-refractory GBM, develop novel and empirical immunotherapeutic paradigms, and undertake preclinical evaluation of candidate therapeutic antibodies using our unique in vivo model of human GBM recurrence" with the goal of generating targeted therapies for GBM patients. [1]

Current projects [1]

  • Preclinical development and evaluation of CAR-T cells targeting CD133 (BTIC marker).
  • Preclinical development and evaluation of CAR-T cells targeting CD70.
  • CRISPR-Cas9 genetic screening to identify targets that act to increase sensitivity of GBM cells to current treatment options.
  • Profile the genetic, protein, and immune environment of a large database of matched primary and recurrent GBM patient samples.
  • Identification of novel targets in the CD133-negative population of GBM.

Brain metastasis

Singh's lab has characterized a rare population of tumor-initiating cells from patient BM samples, which they termed BM-initiating cells (BMICs). Using these BMICs, they have generated preclinical patient-derived xenograft (PDX) mouse models of brain metastases, allowing them to perform genomic studies to identify drivers of pre-metastatic and fully metastatic tumor cell states which they hope will allow them to identify druggable targets in order to uncover new therapies that can prevent and/or eradicate BM. [1]

Current projects [1]

  • Identification of novel genes that regulate the formation of brain metastasis.
  • Functional genomics to characterization the pre- to micro-metastatic states in brain metastasis.
  • Identification of candidate drugs that could target the brain metastatic process, especially those with the potential to translate into the clinic as preventative therapy for primary cancer patients susceptible to brain metastasis.

Support and grants

Singh's lab is supported by the Stem Cell and Cancer Research Institute (SCC-RI), Hamilton Health Sciences, McMaster University, the Brain Tumour Foundation of Canada, Team Kelsey: Brain Tumour Awareness, the Ontario Institute for Cancer Research (OICR), the Brain Canada Foundation, BoxRun, Canadian Cancer Society, American Brain Tumor Association, NSERC CRSNG, Mitacs, CIHR IRSC, Stem Cell Network, The Terry Fox Research Institute (TFRI), Cancer Research Society, Jace Wars, BioCanRx, National Brain Tumor Society, Canada Foundation for Innovation, and Canada Research Chairs. [1]

Singh and her research colleagues won a Terry Fox New Frontiers Program Project Grant from the TFRI in 2016, worth $2.75M over five years. [2]

Selected publications

Personal life

Her hometown is Dundas, Ontario. [2]

Singh is married to Stevan, an architect, and has two sons. [2]

Related Research Articles

<span class="mw-page-title-main">Brain tumor</span> Neoplasm in the brain

A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondary tumors, which most commonly have spread from tumors located outside the brain, known as brain metastasis tumors. All types of brain tumors may produce symptoms that vary depending on the size of the tumor and the part of the brain that is involved. Where symptoms exist, they may include headaches, seizures, problems with vision, vomiting and mental changes. Other symptoms may include difficulty walking, speaking, with sensations, or unconsciousness.

<span class="mw-page-title-main">Metastasis</span> Spread of a disease inside a body

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

<span class="mw-page-title-main">Glioblastoma</span> Aggressive type of brain cancer

Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to unconsciousness.

<span class="mw-page-title-main">Desmoplastic small-round-cell tumor</span> Aggressive and rare cancer

Desmoplastic small-round-cell tumor (DSRCT) is an aggressive and rare cancer that primarily occurs as masses in the abdomen. Other areas affected may include the lymph nodes, the lining of the abdomen, diaphragm, spleen, liver, chest wall, skull, spinal cord, large intestine, small intestine, bladder, brain, lungs, testicles, ovaries, and the pelvis. Reported sites of metastatic spread include the liver, lungs, lymph nodes, brain, skull, and bones. It is characterized by the EWS-WT1 fusion protein.

<span class="mw-page-title-main">Cancer stem cell</span> Cancer cells with features of normal cells

Cancer stem cells (CSCs) are cancer cells that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic (tumor-forming), perhaps in contrast to other non-tumorigenic cancer cells. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are hypothesized to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for patients with metastatic disease.

<span class="mw-page-title-main">Atypical teratoid rhabdoid tumor</span> Medical condition

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Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.

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<span class="mw-page-title-main">Gliosarcoma</span> Medical condition

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<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

<span class="mw-page-title-main">Brain metastasis</span> Cancer that has metastasized (spread) to the brain from another location in the body

A brain metastasis is a cancer that has metastasized (spread) to the brain from another location in the body and is therefore considered a secondary brain tumor. The metastasis typically shares a cancer cell type with the original site of the cancer. Metastasis is the most common cause of brain cancer, as primary tumors that originate in the brain are less common. The most common sites of primary cancer which metastasize to the brain are lung, breast, colon, kidney, and skin cancer. Brain metastases can occur in patients months or even years after their original cancer is treated. Brain metastases have a poor prognosis for cure, but modern treatments are allowing patients to live months and sometimes years after the diagnosis.

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Pediatric ependymomas are similar in nature to the adult form of ependymoma in that they are thought to arise from radial glial cells lining the ventricular system. However, they differ from adult ependymomas in which genes and chromosomes are most often affected, the region of the brain they are most frequently found in, and the prognosis of the patients. Children with certain hereditary diseases, such as neurofibromatosis type II (NF2), have been found to be more frequently afflicted with this class of tumors, but a firm genetic link remains to be established. Symptoms associated with the development of pediatric ependymomas are varied, much like symptoms for a number of other pediatric brain tumors including vomiting, headache, irritability, lethargy, and changes in gait. Although younger children and children with invasive tumor types generally experience less favorable outcomes, total removal of the tumors is the most conspicuous prognostic factor for both survival and relapse.

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Recurrent cancer is a form of cancer that has returned or recurred when a fraction of primary tumor cells evade the effects of treatment and survive in small spaces that are undetectable by diagnostic tests. The initial tumor may become the site of cancer’s return or it may spread to another part of the body. These surviving cells accumulate various genetic changes over time, eventually producing a new tumor cell. It can take up to weeks, months, or even years for cancer to return. Following surgery and/or chemotherapy or radiotherapy, certain tumor cells may persist and develop resistance to treatment and eventually develop into new tumors. Age, sex, cancer type, treatment duration, stage of advancement, and grade of original tumor are some of the factors that determine the rate of cancer recurrence. If recurrent cancer has already moved to other body parts or has developed chemo-resistance then it may be more aggressive than original cancer. In general, the severity of cancer increases with a shorter duration of time between initial treatment and its return.

References