TY - JOUR
T1 - Wound Healing Driver Gene and Therapeutic Development
T2 - Political and Scientific Hurdles
AU - Tang, Xin
AU - Hao, Michelle
AU - Chang, Cheng
AU - Bhatia, Ayesha
AU - O'brien, Kathrine
AU - Chen, Mei
AU - Armstrong, David G.
AU - Li, Wei
N1 - Funding Information:
Cancer is a family of diseases with an incidence rate of 1.7 million and mortality rate of 0.6 million per annum in 2018. The National Cancer Institute (NCI) was founded in 1937. Guided by the National Cancer Act in 1971, which greatly broadened its scope and responsibilities, the NCI has expanded from its initial 15 cancer centers/laboratories to more than 70 research facilities across the United States. The NCI receives 12–18% of the total annual NIH budget in funding as well as funding from numerous other government and non-government agencies: Centers for Disease Control, the National Institute for Environmental Health Sciences, and the American Cancer Society, just to mention a few. Grant applications for cancer research have also been on the rise, with a 46% annual increase compared to less than 10% for the remaining 18 human disease categories.1 Despite the NCI’s massive funding support over the decades, it has faced challenges in delivering on its mission and meeting its own timeline to virtually eradicate cancer, as to date, no drugs have been approved for prevention of tumor metastasis, the main cause of death in cancer patients. The majority of the existing 284 oncology drugs target cell proliferation of primary tumors, extending patients’ survival, but often losing efficacy after several months of treatment due to new mutations in the drug target genes in patients.2 The widely recognized five common steps of cancer progression, including gene mutations, hyperplasia, dysplasia, primary tumor, and metastasis, are highly complex and, therefore, may justify the magnitude of political and financial support that cancer research has received from the public. However, many of these disease mechanisms are by no means wholly unique to cancer. In fact, the mechanisms involved in wound healing have considerable overlap with tumor development, and these two pathologies have widely been considered equal in terms of their complexities. More than 30 years ago, such a connection between tumor environment and wound healing environment was pointed out by Professor Harold Dvorak, who famously described tumors as ‘‘wounds that do not heal.’’3 Like tumors, wounds occur in many different organs in both acute and chronic forms. Mechanistically, wound healing shares a similar degree of complexity with cancer progression, including an intricate series of steps consisting of hemostasis, inflammation, proliferation, and migration, and microenvironmental remodeling, as schematically illustrated and compared in Fig. 1. The best-known example underlying the concept of tumors as wounds that do not heal is perhaps the progression of nonalcoholic liver cancer: fatty liver > liver fibrosis > liver cancer.4,5 However, mechanisms of tumor progression vary greatly among different types of tumors. Our point here is not to downplay the milestones made in cancer research. Instead, we want to raise awareness of the potential higher degree of difficulty for developing wound healing therapeutics (specifically defined here as ‘‘gene target-based’’ therapeutics).
Funding Information:
We thank those who gave us permissions to use their published data in this review article. This study is supported by NIH grants GM066193 and GM067100 (to Wei Li) and grant W81XWH-1810558 from the Congressionally Directed Medical Research Program (to Mei Chen).
Publisher Copyright:
Copyright © 2021 by Mary Ann Liebert, Inc.
PY - 2021/8
Y1 - 2021/8
N2 - Significance: Since the last Food and Drug Administration (FDA) approval of a wound healing therapeutic in 1997, no new therapeutic candidate (excluding physical therapies, devices, dressings, and antimicrobial agents) has advanced to clinical applications. During this period, the FDA drug approvals for tumors, which have been referred to as "wounds that do not heal,"have reached a total of 284 (by end of 2018). Both political and scientific factors may explain this large discrepancy in drug approvals for the two seemingly related and equally complex pathophysiological conditions. Recent Advances: Using the current research funding ratio of 1:150 for wound healing to cancer and the 5% FDA drug approval rate for oncology, we reach a crude estimate of a 0.03% success rate for wound healing therapeutics. Unless a drastic improvement of the current situation, we express a pessimistic outlook toward new and effective wound healing drugs. Critical Issues: We argue that successful development of wound healing therapeutics will rely on identification of wound healing driver genes (WDGs), and the focus should be on WDGs for the wound closure phase of wound healing. Therefore, WDGs must be both necessary and sufficient for wound closure; the absence of a WDG disrupts wound closure, while its supplementation alone is sufficient to restore full wound closure. Successful translation of a WDG into therapeutics requires availability of well-defined animal models with a high degree of relevance to humans. This review discusses the main hurdles faced by the wound healing research community behind the development of so-called "rescuing drugs"for wound healing. Future Directions: Given the lack of new wound healing drugs for the past 23 years, there is a need for a wide range of fresh, innovative, and thorough debates on wound healing drug development, including an organized movement to raise public support for wound healing research.
AB - Significance: Since the last Food and Drug Administration (FDA) approval of a wound healing therapeutic in 1997, no new therapeutic candidate (excluding physical therapies, devices, dressings, and antimicrobial agents) has advanced to clinical applications. During this period, the FDA drug approvals for tumors, which have been referred to as "wounds that do not heal,"have reached a total of 284 (by end of 2018). Both political and scientific factors may explain this large discrepancy in drug approvals for the two seemingly related and equally complex pathophysiological conditions. Recent Advances: Using the current research funding ratio of 1:150 for wound healing to cancer and the 5% FDA drug approval rate for oncology, we reach a crude estimate of a 0.03% success rate for wound healing therapeutics. Unless a drastic improvement of the current situation, we express a pessimistic outlook toward new and effective wound healing drugs. Critical Issues: We argue that successful development of wound healing therapeutics will rely on identification of wound healing driver genes (WDGs), and the focus should be on WDGs for the wound closure phase of wound healing. Therefore, WDGs must be both necessary and sufficient for wound closure; the absence of a WDG disrupts wound closure, while its supplementation alone is sufficient to restore full wound closure. Successful translation of a WDG into therapeutics requires availability of well-defined animal models with a high degree of relevance to humans. This review discusses the main hurdles faced by the wound healing research community behind the development of so-called "rescuing drugs"for wound healing. Future Directions: Given the lack of new wound healing drugs for the past 23 years, there is a need for a wide range of fresh, innovative, and thorough debates on wound healing drug development, including an organized movement to raise public support for wound healing research.
KW - growth factors
KW - Hsp90
KW - necessity and sufficiency
KW - therapeutic
KW - wound closure
KW - wound healing driver gene
UR - http://www.scopus.com/inward/record.url?scp=85108801322&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108801322&partnerID=8YFLogxK
U2 - 10.1089/wound.2019.1143
DO - 10.1089/wound.2019.1143
M3 - Review article
C2 - 32966158
AN - SCOPUS:85108801322
VL - 10
SP - 415
EP - 435
JO - Advances in Wound Care
JF - Advances in Wound Care
SN - 2162-1918
IS - 8
ER -