R41CA261292
Project Grant
Overview
Grant Description
Development of Drug Detoxifying Bacteria for Chemotherapy Induced Gut Injury - Project Summary/Abstract
Irinotecan-based chemotherapy is widely used for the treatment of various types of metastatic cancers. However, severe drug-induced injury or gastrointestinal (GI) toxicity, especially severe delayed-onset diarrhea (SDOD) induced by SN-38 (an active metabolite of irinotecan), limits its clinical application of the drug.
Irinotecan-induced SDOD incidences result in increased healthcare cost due to hospitalization, and poor quality of life and therapeutic outcomes for the cancer patients. Currently, there is no effective treatment available for about ~15% of patients receiving irinotecan therapy, who suffer unmanageable SDOD symptoms, mainly due to their inability to detoxify the SN-38 in the colon.
SN-38 mediated intestinal toxicity was found to be more severe in patients with uridine diphosphate glycosyltransferases 1A1 (UGT1A1) polymorphism, delineating the critical role of colonic UGT1A1 in the prevention of SN-38 induced SDOD.
Various approaches to reduce SN-38 colonic exposure has been tried without much success, and SDOD remains unmanageable dose-limiting toxicity of irinotecan in adult and pediatric cancer patients.
Preliminary research of our academic research collaborators at the University of North Texas and the University of Houston discovered glucosyltransferases from plant Medicago truncatula that could efficiently metabolize typical human UGT1A1 substrates, including SN-38, in an in vitro assay. This led to the novel and innovative concept of bioengineering commensal bacteria E. coli (EC) for overexpressing plant UGT71G1 to create a drug detoxifying bacteria (DDB) that can detoxify SN-38.
In this STTR project, we propose to generate proof-of-concept preclinical evidence in support of developing a safe, efficacious, and traceable DDB as a novel live biotherapeutic product (LBP) to alleviate and/or prevent the SN-38-mediated intestinal toxicity.
Here, we will bioengineer a commensal E. coli strain, with good human gut colonization potential, to overexpress the most active variant of UGT71G1 (U71G1*N) tagged with a green fluorescent protein (GFP), which will be delivered in a protective capsule directly to the colon for the effective glycosylation of SN-38 to SN-38-glucose.
To achieve this goal, the proposed specific aims are:
1) To develop traceable and more active drug detoxifying bacteria EC_U71G1*N (active variant) to detoxify SN-38.
2) To develop a colon-optimized capsule delivery of traceable and highly active lyophilized DDBs.
3) To evaluate the efficacy of 2 colon-delivered DDBs in irinotecan induced SDOD rat model.
An active DDB engineered with PUGT biocatalyst (for the detoxification of SN-38) and GFP (for tracing the effective gut colonization in human feces for therapeutic efficacy monitoring) will accelerate the recovery of cancer patients from SDOD, and lead to the effective management of irinotecan-induced SDOD in clinics.
The success of this project will provide SanarenTero with the proof-of-concept evidence needed for developing an SN-38-targeted traceable DDB for preclinical and IND-enabling studies in a Phase-II SBIR/STTR application.
The novel LBP will act as a complementary therapy to treat SDOD, which should improve the quality of life and even therapeutic outcomes for metastatic cancer patients.
Once successful in this endeavor, we plan to apply the same approach to utilize different plant UGTs for inactivating other GI-toxic drugs, xenobiotics, pollutants, or their toxic metabolites in the colon by developing drug-specific DDB.
Irinotecan-based chemotherapy is widely used for the treatment of various types of metastatic cancers. However, severe drug-induced injury or gastrointestinal (GI) toxicity, especially severe delayed-onset diarrhea (SDOD) induced by SN-38 (an active metabolite of irinotecan), limits its clinical application of the drug.
Irinotecan-induced SDOD incidences result in increased healthcare cost due to hospitalization, and poor quality of life and therapeutic outcomes for the cancer patients. Currently, there is no effective treatment available for about ~15% of patients receiving irinotecan therapy, who suffer unmanageable SDOD symptoms, mainly due to their inability to detoxify the SN-38 in the colon.
SN-38 mediated intestinal toxicity was found to be more severe in patients with uridine diphosphate glycosyltransferases 1A1 (UGT1A1) polymorphism, delineating the critical role of colonic UGT1A1 in the prevention of SN-38 induced SDOD.
Various approaches to reduce SN-38 colonic exposure has been tried without much success, and SDOD remains unmanageable dose-limiting toxicity of irinotecan in adult and pediatric cancer patients.
Preliminary research of our academic research collaborators at the University of North Texas and the University of Houston discovered glucosyltransferases from plant Medicago truncatula that could efficiently metabolize typical human UGT1A1 substrates, including SN-38, in an in vitro assay. This led to the novel and innovative concept of bioengineering commensal bacteria E. coli (EC) for overexpressing plant UGT71G1 to create a drug detoxifying bacteria (DDB) that can detoxify SN-38.
In this STTR project, we propose to generate proof-of-concept preclinical evidence in support of developing a safe, efficacious, and traceable DDB as a novel live biotherapeutic product (LBP) to alleviate and/or prevent the SN-38-mediated intestinal toxicity.
Here, we will bioengineer a commensal E. coli strain, with good human gut colonization potential, to overexpress the most active variant of UGT71G1 (U71G1*N) tagged with a green fluorescent protein (GFP), which will be delivered in a protective capsule directly to the colon for the effective glycosylation of SN-38 to SN-38-glucose.
To achieve this goal, the proposed specific aims are:
1) To develop traceable and more active drug detoxifying bacteria EC_U71G1*N (active variant) to detoxify SN-38.
2) To develop a colon-optimized capsule delivery of traceable and highly active lyophilized DDBs.
3) To evaluate the efficacy of 2 colon-delivered DDBs in irinotecan induced SDOD rat model.
An active DDB engineered with PUGT biocatalyst (for the detoxification of SN-38) and GFP (for tracing the effective gut colonization in human feces for therapeutic efficacy monitoring) will accelerate the recovery of cancer patients from SDOD, and lead to the effective management of irinotecan-induced SDOD in clinics.
The success of this project will provide SanarenTero with the proof-of-concept evidence needed for developing an SN-38-targeted traceable DDB for preclinical and IND-enabling studies in a Phase-II SBIR/STTR application.
The novel LBP will act as a complementary therapy to treat SDOD, which should improve the quality of life and even therapeutic outcomes for metastatic cancer patients.
Once successful in this endeavor, we plan to apply the same approach to utilize different plant UGTs for inactivating other GI-toxic drugs, xenobiotics, pollutants, or their toxic metabolites in the colon by developing drug-specific DDB.
Awardee
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Houston,
Texas
77204
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the End Date has been extended from 08/31/22 to 08/31/23 and the total obligations have increased 14% from $399,955 to $454,955.
Sanarentero was awarded
Project Grant R41CA261292
worth $454,955
from National Cancer Institute in September 2021 with work to be completed primarily in Houston Texas United States.
The grant
has a duration of 2 years and
was awarded through assistance program 93.395 Cancer Treatment Research.
The Project Grant was awarded through grant opportunity PHS 2020-2 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42] Clinical Trial Not Allowed).
SBIR Details
Research Type
STTR Phase I
Title
Development of Drug Detoxifying Bacteria for Chemotherapy Induced Gut Injury
Abstract
PROJECT SUMMARY/ ABSTRACT The overall objective of our predicate STTR Phase I grant (1R41CA261292-01) is to develop a live biotherapeutic product (i.e., a bioengineered bacteria overexpressing a plant enzyme delivered in a protective capsule directly to the colon) for the effective glycosylation of SN-38 to SN-38 glucose for alleviating irinotecan-induced severe delayed-onset diarrhea (SDOD) in the cancer patients. Currently, there is no therapy available to successfully manage the dose-limiting intestinal toxicity (Grade 3 or 4 diarrhea) of irinotecan in about 15% of the patients on standard irinotecan therapy. Moreover, without a solution for effective management of irinotecan-induced SDOD, metastatic refractory cancer patients are unable to maintain the high dose of irinotecan therapy required for their cancer treatment. We believe DDB will allow for better management of SDOD leading to improved quality of life due to reduced severity and incidences of diarrhea, morbidity and mortality due to cessation of chemotherapy, and hospitalization cost. Specific Aims of the predicate phase I STTR application are to 1) develop traceable, safe, and active DDB to detoxify SN-38, 2) develop a colon-optimized capsule delivery of traceable and highly active lyophilized DDBs, and 3) evaluate the safety and efficacy of 2 active DDBs in the irinotecan-induced SDOD rat model. For taking this technology from lab to market faster and successfully, Sanarentero is in the process of developing a viable business model and commercialization strategy including IP portfolio, clinical and regulatory strategies, financing strategies for Randamp;D and business operations, value proposition, product pricing, and strategic partnership with big Pharma. However, we need solid market and customer research in the live biotherpeautics market landscape for developing a realistic path forward. To aid in our efforts in this direction, Sanarentero has put together a 3-member team to participate in the I-Corps at NIH program aims at equipping the SBIR/STTR phase I awardees in the customer discovery research. At the end of this program, we hope to gather sufficient critical learning from conducting customer and stakeholders interviews that will allow us to realign/redefine our current business model and commercialization strategies for maximizing the market success of our DDB.PROJECT NARRATIVE The proposed administrative supplement to STTR phase I award (1R41CA261292-01) for participating in I-Corps at NIH program aims towards learning the customer discovery techniques to assist Sanarentero in the development of a business model and commercialization plan for the novel drug detoxifying bacteria (DDB) efficacious against irinotecan- induced intestinal toxicity. Successful clinical adaptation of DDB will allow for reduction in treatment cost due to severe diarrhea-related hospitalization and improvement in the quality of life of the cancer patients on irinotecan chemotherapy. Additionally, the availability of this product in clinics is expected to increase the overall life expectancy of metastatic cancer patients with refractory/recurrent diseases by allowing the continuation of chemotherapy by preventing the dose-limiting side effects.
Topic Code
102
Solicitation Number
PAR22-073
Status
(Complete)
Last Modified 2/20/24
Period of Performance
9/23/21
Start Date
8/31/23
End Date
Funding Split
$455.0K
Federal Obligation
$0.0
Non-Federal Obligation
$455.0K
Total Obligated
Activity Timeline
Transaction History
Modifications to R41CA261292
Additional Detail
Award ID FAIN
R41CA261292
SAI Number
R41CA261292-2487353254
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Small Business
Awarding Office
75NC00 NIH NATIONAL CANCER INSTITUTE
Funding Office
75NC00 NIH NATIONAL CANCER INSTITUTE
Awardee UEI
VBXLD6X8ZJB4
Awardee CAGE
8FDN1
Performance District
TX-18
Senators
John Cornyn
Ted Cruz
Ted Cruz
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Cancer Institute, National Institutes of Health, Health and Human Services (075-0849) | Health research and training | Grants, subsidies, and contributions (41.0) | $55,000 | 100% |
Modified: 2/20/24