New Castle, New Hampshire, United States
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Articles by Scott J.
Activity
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Today we announced the successful completion of a Series D funding round, raising $130 million and bringing our total valuation to over $1B. The…
Today we announced the successful completion of a Series D funding round, raising $130 million and bringing our total valuation to over $1B. The…
Liked by Scott J. Dylla
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Today, we announced the expansion of our pipeline with a clinical-stage antibody drug conjugate (ADC) targeting PTK7 in solid tumors for adult and…
Today, we announced the expansion of our pipeline with a clinical-stage antibody drug conjugate (ADC) targeting PTK7 in solid tumors for adult and…
Liked by Scott J. Dylla
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I'm proud of my team at Foresite Capital on this milestone. Our thesis has remained remarkably consistent since our inception in 2011, when we…
I'm proud of my team at Foresite Capital on this milestone. Our thesis has remained remarkably consistent since our inception in 2011, when we…
Liked by Scott J. Dylla
Experience & Education
Publications
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A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions
Science Translational Medicine
Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non–small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC…
Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non–small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC, OVCA, and NSCLC patient–derived xenografts (PDXs). To deliver a potent anticancer drug to PTK7-expressing TICs, we generated a targeted antibody-drug conjugate (ADC) composed of a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline–based linker, and Aur0101, an auristatin microtubule inhibitor. The PTK7-targeted ADC induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of TICs, as determined by serial transplantation experiments. In addition to reducing the TIC frequency, the PTK7-targeted ADC may have additional antitumor mechanisms of action, including the inhibition of angiogenesis and the stimulation of immune cells. Together, these preclinical data demonstrate the potential for the PTK7-targeted ADC to improve the long-term survival of cancer patients.
Other authorsSee publication -
Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study
The Lancet Oncology
Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identifi ed in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen.
Other authorsSee publication -
Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer
Cell Reports
Small cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC…
Small cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC are linked to TPCs. SCLC TPCs possess a distinct transcriptional profile compared to non-TPCs, including elevated MYC activity. Genetic and pharmacological inhibition of MYC in SCLC cells to non-TPC levels inhibits long-term propagation but not short-term growth. These studies identify a highly tumorigenic population of SCLC cells in mouse models, cell lines, and patient tumors and a means to target them in this most fatal form of lung cancer.
Other authorsSee publication -
Toppling High-Grade Pulmonary Neuroendocrine Tumors with a DLL3-Targeted Trojan Horse
Molecular & Cellular Oncology
Delta-like protein 3 (DLL3) is a novel and tractable tumor-initiating cell-associated target for the antibodydrug conjugate SC16LD6.5 in high-grade pulmonary neuroendocrine tumors. Elevated expression of DLL3, an inhibitor of Notch pathway activation, marks the second recent observation that impairment of Notch receptor signaling may play a critical role in neuroendocrine tumorigenesis.
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A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo
Science Translational Medicine
The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX…
The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.
Other authorsSee publication -
Anti-EFNA4 Calicheamicin Conjugates Effectively Target Triple-Negative Breast and Ovarian Tumor-Initiating Cells To Result In Sustained Tumor Regressions
Clinical Cancer Research
Purpose: Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival.
Experimental Design: A panel of well-annotated patient-derived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TIC were queried…Purpose: Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival.
Experimental Design: A panel of well-annotated patient-derived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TIC were queried for overexpressed antigens, one of which was selected to be the target of an antibody-drug conjugate (ADC). The efficacy of the ADC was evaluated in 15 PDX models to generate hypotheses for patient stratification.
Results: We herein identified E-cadherin (CD324) as a surface antigen able to reproducibly enrich for TIC in well annotated, low passage TNBC and ovarian cancer PDXs. Gene expression analysis of TIC led to the identification of Ephrin-A4 (EFNA4) as a prospective therapeutic target. An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA damaging agent calicheamicin achieved sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. Non-claudin low TNBC tumors exhibited higher expression and more robust responses than other breast cancer subtypes, suggesting a specific translational application for tumor sub-classification.
Conclusions: These findings demonstrate the potential of PF-06647263 (anti-EFNA4-ADC) as a first-in-class compound designed to eradicate TIC. The use of well-annotated PDX for drug discovery enabled the identification of a novel TIC target, pharmacological evaluation of the compound, and translational studies to inform clinical development.Other authorsSee publication -
Initiation and Characterization of Small Cell Lung Cancer Patient-Derived Xenografts from Ultrasound-Guided Transbronchial Needle Aspirates
PLOS One
Small cell lung cancer (SCLC) is a devastating disease with limited treatment options. Due to its early metastatic nature and rapid growth, surgical resection is rare. Standard of care treatment regimens remain largely unchanged since the 1980’s, and five-year survival lingers near 5%. Patient-derived xenograft (PDX) models have been established for other tumor types, amplifying material for research and serving as models for preclinical experimentation; however, limited availability of primary…
Small cell lung cancer (SCLC) is a devastating disease with limited treatment options. Due to its early metastatic nature and rapid growth, surgical resection is rare. Standard of care treatment regimens remain largely unchanged since the 1980’s, and five-year survival lingers near 5%. Patient-derived xenograft (PDX) models have been established for other tumor types, amplifying material for research and serving as models for preclinical experimentation; however, limited availability of primary tissue has curtailed development of these models for SCLC. The objective of this study was to establish PDX models from commonly collected fine needle aspirate biopsies of primary SCLC tumors, and to assess their utility as research models of primary SCLC tumors. These transbronchial needle aspirates efficiently engrafted as xenografts, and tumor histomorphology was similar to primary tumors. Resulting tumors were further characterized by H&E and immunohistochemistry, cryopreserved, and used to propagate tumor-bearing mice for the evaluation of standard of care chemotherapy regimens, to assess their utility as models for tumors in SCLC patients. When treated with Cisplatin and Etoposide, tumor-bearing mice responded similarly to patients from whom the tumors originated. Here, we demonstrate that PDX tumor models can be efficiently established from primary SCLC transbronchial needle aspirates, even after overnight shipping, and that resulting xenograft tumors are similar to matched primary tumors in cancer patients by both histology and chemo-sensitivity. This method enables physicians at non-research institutions to collaboratively contribute to the rapid establishment of extensive PDX collections of SCLC, enabling experimentation with clinically relevant tissues and development of improved therapies for SCLC patients.
Other authorsSee publication -
Patient-Derived Xenografts, the Cancer Stem Cell Paradigm, and Cancer Pathobiology in the 21st Century
Laboratory Investigation
Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer’s secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional…
Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer’s secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls
for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer.Other authorsSee publication -
DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency
Cell Stem Cell
Previous studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xenograft models derived from primary human tumors. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more…
Previous studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xenograft models derived from primary human tumors. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. Treatment with anti-human DLL4 inhibited the expression of Notch target genes and reduced proliferation of tumor cells. Furthermore, we found that specifically inhibiting human DLL4 in the tumor, either alone or in combination with the chemotherapeutic agent irinotecan, reduced cancer stem cell frequency, as shown by flow cytometric and in vivo tumorigenicity studies.
Other authorsSee publication -
Cancer Stem Cells
Emerging Technology Platforms for Stem Cells (John Wiley & Sons, Inc.)
The cancer stem cell (CSC) hypothesis has, over the past several years, enjoyed
an intense resurgence of interest from investigators probing the underlying
mechanisms of carcinogenesis. Although originally proposed to exist in the
late 1960s (1), the concept of tumor stem cells as an underpinning force of
tumor biology was forgotten, and the technology to identify and isolate these
cells was nonexistent, until recently (2–4). The CSC theory posits that only
stem cells persist…The cancer stem cell (CSC) hypothesis has, over the past several years, enjoyed
an intense resurgence of interest from investigators probing the underlying
mechanisms of carcinogenesis. Although originally proposed to exist in the
late 1960s (1), the concept of tumor stem cells as an underpinning force of
tumor biology was forgotten, and the technology to identify and isolate these
cells was nonexistent, until recently (2–4). The CSC theory posits that only
stem cells persist long enough to accumulate the set of mutations required to
tip normal differentiation in favor of abnormal growth, and hence spontaneously
arising human tumors likely arise from deregulation of stem or progenitor
cell populations. In this paradigm, tumors are best conceptualized not as a
clone of unstable cells with aberrant growth control, but more nearly as normal
development gone haywire. More to the point, many cancers appear to result
from stem cells that anchor the base of a differentiation program responsible
for tissue regeneration and homeostasis, but have lost essential constraints on
growth, differentiation, and/or localization. -
Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy
PLoS One
CoCSC are enriched in colon tumors following chemotherapy and remain capable of rapidly regenerating tumors from which they originated. By focusing on the biology of CoCSC, major resistance mechanisms to specific chemotherapeutic agents can be attributed to specific genes, thereby suggesting avenues for improving cancer therapy.
More activity by Scott J.
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It’s a bad day to be a pathogenic immune cell. Congratulations to the newest a16z Bio + Health portfolio company, Santa Ana Bio, Inc., on their…
It’s a bad day to be a pathogenic immune cell. Congratulations to the newest a16z Bio + Health portfolio company, Santa Ana Bio, Inc., on their…
Liked by Scott J. Dylla
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At NewLimit we started with de-aging your immune cells. Now we are expanding into de-aging your liver. Adding serial biotech founder Markus Grompe to…
At NewLimit we started with de-aging your immune cells. Now we are expanding into de-aging your liver. Adding serial biotech founder Markus Grompe to…
Liked by Scott J. Dylla
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Excited to see the investment in an end-to-end ADC manufacturing facility that we are building in Singapore. ADC manufacture requires a multi-step…
Excited to see the investment in an end-to-end ADC manufacturing facility that we are building in Singapore. ADC manufacture requires a multi-step…
Liked by Scott J. Dylla
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News Update: Genmab Completes Acquisition of ProfoundBio. As part of the Genmab team, we remain committed to developing novel antibody-based…
News Update: Genmab Completes Acquisition of ProfoundBio. As part of the Genmab team, we remain committed to developing novel antibody-based…
Liked by Scott J. Dylla
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We’re delighted to announce our Centre for Insect Technology is open and to celebrate this milestone we invited our investors, policy-makers and…
We’re delighted to announce our Centre for Insect Technology is open and to celebrate this milestone we invited our investors, policy-makers and…
Liked by Scott J. Dylla
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Several years ago, Theresa noticed a knot in her right breast, but at the time, she was caring for her mother and delayed visiting her doctor…
Several years ago, Theresa noticed a knot in her right breast, but at the time, she was caring for her mother and delayed visiting her doctor…
Liked by Scott J. Dylla
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Happy International Women’s Day! Thank you to World ADC Event Series for using the recognition I received for long-standing achievement as a platform…
Happy International Women’s Day! Thank you to World ADC Event Series for using the recognition I received for long-standing achievement as a platform…
Liked by Scott J. Dylla
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So great to talk to my good friend and long time collaborator David Weisburd at 10X Capital about Alloy Therapeutics, Inc. and our affiliated venture…
So great to talk to my good friend and long time collaborator David Weisburd at 10X Capital about Alloy Therapeutics, Inc. and our affiliated venture…
Liked by Scott J. Dylla
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Grateful to give an invited talk at the 6th Annual Treg-Directed Therapies Summit! Please join us in Boston this May 21-23. https://lnkd.in/gXZEXvwC
Grateful to give an invited talk at the 6th Annual Treg-Directed Therapies Summit! Please join us in Boston this May 21-23. https://lnkd.in/gXZEXvwC
Liked by Scott J. Dylla
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