Accelerating glioblastoma therapeutics via venture philanthropy

Siah, Kien Wei; Xu, Qingyang; Tanner, Kirk; Futer, Olga; Frishkopf, John J.; Lo, Andrew W.

doi:10.1016/j.drudis.2021.03.020

Cited by 11 publications

(5 citation statements)

References 8 publications

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“…In addition to the original application to cancer, the megafund structure has also been proposed as a funding model for more targeted therapeutics, including pediatric cancer (Das et al 2018), ovarian cancer (Chaudhuri et al 2019), brain cancer (Siah et al 2021b), and rare diseases (Fagnan et al 2014(Fagnan et al , 2015, the latter of which is discussed in more detail in the next section. In each of these cases, the simulations show that at sufficient scale, the expected returns and risk of a megafund are comparable with or better than traditional financial investments such as stocks, mutual funds, exchange-traded funds, and other common risky assets.…”

Section: Financial Innovationmentioning

confidence: 99%

“…More direct evidence for the feasibility of unique financing strategies to facilitate rare disease therapeutics is provided by several case studies spanning multiple diseases and organizations: cystic fibrosis and the Cystic Fibrosis Foundation (CFF) (Kim & Lo 2019), Duchenne muscular dystrophy and Solid Biosciences (Kim & Lo 2016), AADC (aromatic l-amino acid decarboxylase) deficiency and Agilis Biotherapeutics (Das, Huang & Lo 2019), and glioblastoma and the National Brain Tumor Society (Siah et al 2021b).…”

Section: Rare Disease Megafundsmentioning

confidence: 99%

“…In addition, philanthropic organizations can provide scientific assistance-access to disease experts, patient registries, natural history studies, and other critical resources-to derisk the drug development process. Siah et al (2021b) provide a current example with the National Brain Tumor Society and the resources they bring to their impact fund to treat glioblastoma. Alvarez & Lo (2022) provide a more general perspective on how VP can facilitate biomedical innovation and provide mini-case studies of three VP initiatives-the JDRF T1D Fund for type 1 diabetes research, the MPM Oncology Impact Fund, and the American Heart Association's Cardeation Capital TM -as examples.…”

Section: Venture Philanthropy and Other Organizational Innovationsmentioning

confidence: 99%

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Financing Biomedical Innovation

Thakor

2022

Annu. Rev. Financ. Econ.

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We review the recent literature on financing biomedical innovation, with a specific focus on the drug development process and how it may be enhanced to improve outcomes. We begin by laying out stylized facts about the structure of the drug development process and its associated costs and risks, and we present evidence that the rate of discovery for life-saving treatments has declined over time while costs have increased. We make the argument that these structural features require drug development (i.e., biopharmaceutical) firms to rely on external financing and at the same time amplify market frictions that may hinder the ability of these firms to obtain financing, especially for treatments that may have large societal value relative to the benefits going to the firms and their investors. We then provide an overview of the evidence for various types of market frictions to which these drug development firms are exposed and discuss how these frictions affect their incentive to invest in the development of new drugs, leading to underinvestment in valuable treatments. In light of this evidence, numerous studies have proposed ways to overcome this funding gap, including the use of financial innovation. We discuss the potential of these approaches to improve outcomes.

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Section: Financial Innovationmentioning

confidence: 99%

Section: Rare Disease Megafundsmentioning

confidence: 99%

Section: Venture Philanthropy and Other Organizational Innovationsmentioning

confidence: 99%

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Financing Biomedical Innovation

Thakor

2022

Annu. Rev. Financ. Econ.

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“…Only one article discussed the implications of this trend and advocated that NPOs should refrain from seeking commercial control over the by‐products of the research because this practice would heighten pressures to commercialize 58 . The authors’ position conflicts, however, with the emerging practice of venture philanthropy, 59 which has shown to be highly successful for therapy development in cystic fibrosis 60 and glioblastoma 61 …”

Section: Dissemination Reporting and Outreachmentioning

confidence: 99%

“…Few articles discussed how NPO responsibilities blur when stakeholders belong to multiple groups or how NPO responsibilities change, if at all, when they have financial interests in the commercialization of a drug. Measurable returns in NPO investment in trials that led to drug development for other pediatric diseases60,61,64 accentuate the need for consistent conflicts of interest disclosure, arm's-length recruitment strategies, and commitments to transparent trial reporting and data sharing if such models are to scale in the pediatric cancer space. Future empirical research could address these gaps by surveying NPOs about how they make research funding decisions and the ethical issues they encounter.…”

mentioning

confidence: 99%

A systematic literature review to identify ethical, legal, and social responsibilities of nonprofit organizations when funding clinical trials in pediatric cancer

Rahimzadeh

Wolfert

Buenger

et al. 2022

Pediatric Blood & Cancer

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Nonprofit organizations (NPOs) play critical roles as funding sources, research partners, and disseminators of drug developments in pediatric cancer. Yet the literature provides limited guidance about ethical best practices when NPOs make trial funding decisions in this space. We conducted a systematic review of the literature indexed in PubMed and Web of Science to identify the ethical, legal, and social responsibilities of NPOs to four key stakeholder groups in funding pediatric cancer trials: (i) patients/families, (ii) researchers, (iii) industry sponsors, and (iv) donors. We applied the lifecycle framework for patient engagement in drug research and development proposed by Geissler and colleagues to analyze themes related to NPOs' responsibilities across 54 articles that met our inclusion criteria. Emergent themes included transparency surrounding conflicts of interest, the rigor of scientific review, and communication with patients/communities about trial progress. Our research identified critical gaps in best practices for negotiating research partnerships, managing competing research priorities, and pursuing alternative financing models including venture philanthropy. Results from our review informed a set of best practices to guide NPOs in making trial funding decisions that align with stakeholder values and interests.

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Functional profiling of murine glioma models highlights targetable immune evasion phenotypes

Mikolajewicz,

Tatari,

Wei

et al. 2024

Acta Neuropathol

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Cancer-intrinsic immune evasion mechanisms and pleiotropy are a barrier to cancer immunotherapy. This is apparent in certain highly fatal cancers, including high-grade gliomas and glioblastomas (GBM). In this study, we evaluated two murine syngeneic glioma models (GL261 and CT2A) as preclinical models for human GBM using functional genetic screens, single-cell transcriptomics and machine learning approaches. Through CRISPR genome-wide co-culture killing screens with various immune cells (cytotoxic T cells, natural killer cells, and macrophages), we identified three key cancer-intrinsic evasion mechanisms: NFκB signaling, autophagy/endosome machinery, and chromatin remodeling. Additional fitness screens identified dependencies in murine gliomas that partially recapitulated those seen in human GBM (e.g., UFMylation). Our single-cell analyses showed that different glioma models exhibited distinct immune infiltration patterns and recapitulated key immune gene programs observed in human GBM, including hypoxia, interferon, and TNF signaling. Moreover, in vivo orthotopic tumor engraftment was associated with phenotypic shifts and changes in proliferative capacity, with murine tumors recapitulating the intratumoral heterogeneity observed in human GBM, exhibiting propensities for developmental- and mesenchymal-like phenotypes. Notably, we observed common transcription factors and cofactors shared with human GBM, including developmental ( Nfia and Tcf4 ), mesenchymal ( Prrx1 and Wwtr1 ), as well as cycling-associated genes ( Bub3 , Cenpa , Bard1 , Brca1 , and Mis18bp1 ). Perturbation of these genes led to reciprocal phenotypic shifts suggesting intrinsic feedback mechanisms that balance in vivo cellular states. Finally, we used a machine-learning approach to identify two distinct immune evasion gene programs, one of which represents a clinically-relevant phenotype and delineates a subpopulation of stem-like glioma cells that predict response to immune checkpoint inhibition in human patients. This comprehensive characterization helps bridge the gap between murine glioma models and human GBM, providing valuable insights for future therapeutic development. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-024-02831-w.

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Accelerating glioblastoma therapeutics via venture philanthropy

Cited by 11 publications

References 8 publications

Financing Biomedical Innovation

Financing Biomedical Innovation

A systematic literature review to identify ethical, legal, and social responsibilities of nonprofit organizations when funding clinical trials in pediatric cancer

Functional profiling of murine glioma models highlights targetable immune evasion phenotypes

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