Study Using Patient-Derived Cells Within Human Extracellular Matrix (ECM) to Replicate Heterogeneous Tumor Microenvironments Aims to Improve Breast and Ovarian Cancer Treatment by Decreasing Anti-cancer Drug Failure Rates on a Large-Scale SCOTTSDALE, AZ–(Marketwired – March 30, 2016) – Lattice Biologics Ltd. (TSX VENTURE: LBL)(OTCBB: BLVKF) (“Lattice Biologics” or the “Company”) is pleased to announce it has … Continued
Study Using Patient-Derived Cells Within Human Extracellular Matrix (ECM) to Replicate Heterogeneous Tumor Microenvironments Aims to Improve Breast and Ovarian Cancer Treatment by Decreasing Anti-cancer Drug Failure Rates on a Large-Scale
SCOTTSDALE, AZ–(Marketwired – March 30, 2016) – Lattice Biologics Ltd. (TSX VENTURE: LBL)(OTCBB: BLVKF) (“Lattice Biologics” or the “Company”) is pleased to announce it has entered into an Industry Sponsored Collaboration Agreement with Sunnybrook Research Institute (“SRI”) in Toronto, Ontario titled, “Conditional Reprogramming of Epithelial Cells to Determine Mechanisms of Resistance and Drug Sensitivity” (the “Study”). The purpose of the Study is to develop new research methods, including the creation of new instruments to make cellular measurements, and the validation of methods to determine mechanisms of resistance and drug sensitivity. The successful identification of such new methods would lead to commercialization of high content screening (HCS) chemosensitivity testing for cancer patients.
“We are extremely pleased to be working with such a prestigious partner as Sunnybrook Research Institute to develop a personalized approach for cancer diagnostics,” states Guy Cook, Chief Executive Officer of Lattice Biologics Ltd.
“Lattice Biologic’s ECM technology is revolutionary in its unparalleled ability to accurately recreate complex tumor microenvironments because it allows us to grow biopsies from patients’ own cancer tumors in the laboratory, subject the tumors to multiple anti-cancer agents, and observe the resulting behaviors all while sustaining natural conditions.
“This will provide a never-before-seen understanding of how individual patients’ tumors respond to specific treatments, allowing physicians to prescribe anti-cancer treatments with new accuracy. This level of personalized medicine will change the entire cancer treatment game.
“Most people you meet have already felt the devastating sting of cancer somewhere in their life,” continued Cook. “I am personally motivated to improve outcomes by advancing diagnostic techniques as my father passed from lung cancer in 1981, my aunt from pancreatic cancer in 1982, and my sister — also from pancreatic cancer — in 1991. As such, the opportunity to contribute to Dr. Andrews’ cutting edge diagnostic research with our ECM technology is both humbling and personally fulfilling.”
KEY STUDY PARTIES:
- Sunnybrook Research Institute (SRI) (The “Institution”) in Toronto, Ontario, Canada is where the Study will take place.
- David Andrews, Ph.D., (The “Principal Investigator”) (Director and Senior Scientist, Biological Sciences – Sunnybrook Research Institute; Professor, Department of Biochemistry – University of Toronto; Canada Research Chair in Membrane Biogenesis) will be responsible for the proper conduct of the Study and assume medical and regulatory responsibility for any procedures occurring at the Institution.
- Lattice Biologics Ltd. (The “Sponsor”) based in Scottsdale, AZ, USA, takes responsibility for the initiation, management, and financing of the Study.
COMBATING FAILURES IN CURRENT RESEARCH MODELS:
Mounting evidence shows that drug failure rates for cancer is greater than any other therapeutic areas, with approximately 93% of anticancer agents not obtaining licenses even though they show promise in the pre-clinical development phases1. This is largely due to the suboptimal conditions under which new therapies are tested in preclinical disease models: either cell lines (cell cultures developed/cloned from a single cell, consisting only of cells with a uniform genetic makeup) or animal models. Cell lines and animal models cannot represent primary tumors in the context of drug resistance and tumor heterogeneity (diversity) and lack the wide range of molecular transformation events present in human tumors, which can produce misleading results. For example, the effects of the tumor microenvironment on drug responses do not always represent human primary tumors because the stromal component of animal derived tumors differs from humans in both its composition and properties1.
The often-false indications of efficacy for potential therapeutic agents provided by cell lines and animal models in Phase II clinical trials indicate the need for another model that recapitulates the true behavior of human primary tumors in the body2. To overcome these hurdles, new disease models must be based on human biomaterials that more accurately mimic the disease of interest.
BACKGROUND: Chemosensitivity and Personalized Medicine
The goal of chemosensitivity testing is to provide a rapid, comprehensive, and actionable analysis of drug-induced responses in cancer cells by approved and investigational drugs or drug combinations in individual patient tumor specimens.
Traditional cancer treatment methods have relied largely on physician hypothesis for medication plans and are not pre-tested according to each individual patient’s unique conditions. Although physicians have begun to select cancer treatments specific to certain patient populations based on the molecular characteristics of tumors, these advances have often failed to generate reliable clinical responses to treatment. Results remain unpredictable and positive responses are often short-lived. Scientists frequently cite the failure to properly imitate the heterogeneous cellular microenvironment and genetic instability of patient tumors as the basis for this unpredictability in existing pre- clinical treatment models.
The lack of available personalized tumor response data prior to prescription can lead to the selection of medication with reduced healing potential and result in discouraging drug resistances. In that event, the patient’s own weakened body becomes an experimental environment where the complex web of drug impacts plays out as the patient undergoes one strenuous chemical treatment after another in a potentially deadly game of guess-and-check.
Nowhere is speed and accuracy more critical than in the case of an aggressive disease. The more time that passes while trying to identify an effective medication strategy, the more the patient’s immune system and overall health can become compromised.
PURPOSE: Increased Accuracy, Speed, and Patient Health
The penultimate goal of the Study is to remove cancer patients from the medical “guinea pig” treatment process. This will be accomplished by developing new high-throughput research methods to screen tumor cells that have been sampled and cultivated within a clinical laboratory setting that closely mimics the tumor’s natural environment to enable the most accurate chemosensitivity determinations prior to patient treatment.
The realistic ECM-produced microenvironment has the potential to offer an unparalleled view into individual cancer tumors’ cellular behavior, while high-throughput / high content screening methods are poised to lend life-saving speed to the process and also increase cost effectiveness. As envisioned, this clinical demonstration will be invaluable for understanding how patients would respond to a wide range of medications prior to beginning treatment.
The Study’s hypothesis poses that accurate disease models based on human tumor cell biopsies are critical to understanding the pathophysiology of cancers and decreasing high anti-cancer drug failure rates.
PROPOSED RESEARCH: Breast and Ovarian Cancer
Progress has been made in developing patient-derived xenograft (PDX) models as an alternative to the existing unreliable pre-clinical cancer treatment models; however, PDX are limited by high cost, variable engraftment rates, and a significant time burden required for generation and gestation in immunodeficient mice. Therefore, PDX models have their own limited clinical utility in personalizing cancer medicine, which compels the scientific community to develop new approaches. At the forefront of this effort, Dr. Andrews’ group has successfully utilized chemosensitivity for Chronic lymphocytic leukemia (CLL) in an in vitro model of the leukemic microenvironment that is amenable to high content image-based screening.
This Study seeks to extend Dr. Andrews’ successful research in leukemia patient cells by using the Opera High Content Screening System to image patient-derived breast and ovarian cancer cells. The cells will be grown as 2D and 3D tumor organoids (three- dimensional organ buds grown in vitro) via conditional re-programming with a Rho- associated kinase inhibitor.
The Study will adapt and optimize existing technology for breast and prostate cancers, including the novel use of human rather than mouse stroma for the growth media. Ultimately, the goal is development of a rigorous and cost-effective tumor model which will allow investigations into tumoral heterogeneity, predict patient sensitivity to new and existing therapies, and enable the study of mechanisms of drug resistance in a clinically relevant timely manner.
New high content image analysis techniques and non-toxic Multichrome dyes developed at SRI permit analysis of cellular responses to drugs in primary patient cells using an Opera screening instrument. Currently, software is being developed to take further advantage of the Multichrome dyes. This software combines data from temporal changes in both the localization and spectral properties of the dyes. By measuring the fluorescence of the dyes at two different wavelengths simultaneously and analyzing changes in dye distribution using texture features, it is possible to identify changes in the physiology of cells in response to drugs.
Dr. Andrews is using these complex dyes and image feature analysis to assess chemosensitivity in a more holistic fashion than simply measuring cell death or proliferation as is done in commercial assays. The readout of these assays can be traced to specific metabolic pathways gone awry, indicating which particular anti-cancer agents would have the most beneficial impacts on the cells. Importantly, the use of these dyes also reduces the cost of chemosensitivity assays from more than $500 per each 384- well imaging plate to less than $50. Research is planned to validate the use of these dyes pre-clinically for chemosensitivity assays for CLL (in progress) and for cells from biopsy samples from breast and ovarian tumors. The success of these studies is expected to lead to new clinical trials.
ADDITIONAL RESEARCH TEAM MEMBERS:
Four clinician scientists are collaborating with Dr. Andrews to develop new HCS approaches for chemosensitivity testing:
- David Spaner: Clinician scientist at SRI that has made major contributions to the understanding and treatment of chronic lymphocytic leukemia. He publishes regularly in the top (impact factor >10) hematology journals including Blood and Leukemia. He is currently funded by two CIHR grants and by industry.
- Helen MacKay: Head of the Division of Medical Oncology & Hematology at the Sunnybrook Odette Cancer Centre, co-chair of the Ovarian Group of the NCIC Clinical Trials Group, Senior Scientist at SRI, and a member of numerous international ovarian cancer translational committees including the Translational Committee of the Gynecologic Cancer Intergroup (GCIG). Helen brings extensive experience in translational ovarian cancer research (particularly in relation to clinical trials samples) and has coordinated the development pre-clinical PDX models. She will spearhead rapidly incorporating these models into clinical trial design.
- Gregory Czarnota: Chief of Radiation Oncology at Sunnybrook Health Sciences Centre, Research Director and Senior Scientist in the Odette Cancer Program at SRI, and Associate Professor in the Departments of Radiation Oncology and Medical Biophysics at the University of Toronto. Samples will be obtained from breast cancer patients undergoing neoadjuvant therapy for chemosensitivity analysis and then monitored for drug response using ultrasound methods developed by Dr. Czarnota and again by pathology at the time of surgery. This will enable determining the prognostic value of chemosensitivity analysis for patients undergoing neoadjuvant therapy prior to surgery.
- Wedad Hanna: Staff Pathologist at Sunnybrook Hospital will provide pathology support for these studies.
The Study will be conducted at the Institution’s facilities in Toronto, Ontario, Canada and will be conducted in compliance with all applicable laws and regulations and according to established ethical, medical and scientific standards, including the Canada Food and Drugs Act and all regulations made pursuant thereto, Good Clinical Practice (GCP) as per the ICH-Harmonized Tripartite Guideline for Good Clinical Practice, the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, December 2010 (“TCPS2”), and the Declaration of Helsinki (DoH), and in compliance with all applicable guidelines governing research involving human subjects. The Study is planned to be completed within two years.
1Hutchinson, L. and Kirk, R. (2011) High drug attrition rates-where are we going wrong?
Nature Reviews/Clinical Oncology 8:189-190.
2Marshall, J.C. (2014) Why have clinical trials in sepsis failed? Trends Molecular Medicine 20 (4):195-203.
About Lattice Biologics Ltd.:
Lattice Biologics recently completed its RTO, becoming a publically traded company on January 4, 2016 and is traded on the TSX-V under the symbol: LBL. The Company is an emerging personalized/precision medicine leader in the field of cellular therapies and tissue engineering, with a focus on bone, skin, and cartilage regeneration.
Lattice Biologics develops and manufactures biologic products to domestic and international markets. Lattice’s products are used in a variety of applications, including:
- Enhancing fusion in spine surgery
- Enhancing breast reconstruction post mastectomy for breast cancer patients
- Sports medicine indications, including ACL repair
- Promotion of bone regeneration in foot and ankle surgery
- Promotion of skull healing following neurosurgery
- Enhancing wound repair in burn victims
- Subchondral bone defect repair in knee and other joint surgeries
Lattice Biologics maintains headquarters, laboratory and manufacturing facilities in Scottsdale, Arizona as well as offices in Toronto Ontario. The facility includes ISO Class 1000 and ISO Class 100 clean rooms, and specialized equipment capable of crafting traditional allografts and precision specialty allografts for various clinical applications.
The Lattice Biologics organization includes a product development and scientific research team of Ph.D.’s, highly trained tissue bank specialists, surgical technicians, certified sterile processing and distribution technicians, and CNC operators who maintain the highest standards of aseptic technique throughout each step of the manufacturing process. From donor acceptance to the final packaging and distribution of finished allografts, Lattice is committed to maintaining the highest standards of allograft quality, innovation, and customer satisfaction.
Lattice Biologics maintains all necessary licensures to process and sell its tissue engineered products within the U.S. and internationally. This includes Certificates to Foreign Governments from the U.S. Food and Drug Administration (FDA) and registrations for 29 countries, which allow the export of bone, tendon, meniscus, ligament, soft tissue, and cartilage products outside of the U.S.
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