Lessons Learned in T1 Research: mouse to human Jean Y. Tang MD PhD Assistant Professor Department of...
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![Page 1: Lessons Learned in T1 Research: mouse to human Jean Y. Tang MD PhD Assistant Professor Department of Dermatology.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649d415503460f94a1c433/html5/thumbnails/1.jpg)
Lessons Learned in T1 Research: mouse to human
Jean Y. Tang MD PhD
Assistant Professor
Department of Dermatology
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Mechanism of disease
In vitro experiments
Animal studies
Human clinical trials
Epidemiological studies
New drugs
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Lessons learned: challenges
• Jack of all trades, Master of none– Journals– Conferences– Students and trainees
• Not that many role models – find a true believer and the experts
Slower time to publication
Grants: enthusiasm from NIH
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KL2/K23 Mentors: – Ervin Epstein, Children’s Hospital Oakland
Research Institute– Mary-Margaret Chren, Dept of
Dermatology, UCSF– Charles McCulloch, Steve Cummings, Dept
of Epidemiology and Biostatistics, UCSF
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Clinical trialsin PTCH1 +/-
BCNS patients
Observational studies at Kaiser/UCSF
Screen for drugs in cell lines andPtch1+/- mice
Translational Research in BCC
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In vitro MiceObservational
studies Clinical
Trials
Celecoxib (oral) ↓ ↓ mixed ↓ in subset
Statin No No No N/A
Vitamin D3 ↓↓ ↓↓ ↓ Biomarker study
Hh Antagonist (Genentech)
↓↓↓ ↓↓↓↓ none Enrolling RCT
Itraconazole (antifungal)
↓↓ ↓↓ none Biomarker study
Summary of chemopreventive agents against BCCs
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Challenge Lesson Learned
Celecoxib (oral) Combining mouse and RCT Statistics, finding the experts
StatinsDifficulty in combining mouse and epidemiologic results (Kaiser)
OK to disagree
Vitamin D3Difficulty of doing it all yourself: lab, mouse, pilot clinical trial
-1°Mentor and his lab -SFCC, EpiBio mentors
-Public databases
Hh Antagonist Collaborations with Genentech-Good to have lab skills
-RCT design
Itraconazole Collaborations with basic lab
FDA approved drug
-Nice to collaborate
-Time to start the pilot trial
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Epidemiology of BCC
• 1 million BCC cases per yr in US• Estimated annual incidence of 0.1% to 0.5% • Rare risk of metastasis: < 0.5%
• 5th most costly cancer for Medicare
• The age-adjusted incidence per 100,000 white individuals: 475 cases in men, 250 cases in women
• The estimated lifetime risk of BCC in the white population is 33-39% in men and 23-28% in women.
• Risk of second BCC: 44% in 3 yr
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BCC basic science:
• Almost all BCCs have mutations in PTCH1 tumor suppressor gene
• All BCCs have increased Hedgehog signaling
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Ptch
Smo
Gli off
HH
Ptch
Smo
Gli on
Mutant Ptch
Smo
Gli on
CPN
Smo
Gli off
Ptch
Smo
Gli off
Ptch
Smo
Gli off
HH
Ptch
Smo
Gli on
HH
Ptch
Smo
Gli on
Mutant Ptch
Smo
Gli on
Mutant Ptch
Smo
Gli on
Smo
Gli
Hedgehog signaling pathway regulates cell proliferation and growth
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Basal cell nevus syndrome
Basal cell nevus syndrome are PTCH1+/-
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Ptch1+/- mice mimic BCNS phenotype: develop BCC tumors after IR or UV treatment
Goodrich and Scott, Science 1997Aszterbaum, Oro, Scott, Epstein Nature Medicine 1999
(A) Photo of multiple circled BCCs on the back of a patient with Basal Cell Nevus Syndrome. (B) Photo of Ptch1+/- K14-Cre-ER2 p53 fl/fl mice with multiple BCCs
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Mechanism of disease
In vitro experiments
Animal models
Human clinical trials
Hedgehog pathway
BCC cell lines
Ptch1 +/- mice
PTCH1+/- Basal cell nevus syndrome patients
Roadmap for finding new therapeutics
Epidemiological studiesPatients with sporadic
BCCs
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In vitro MiceObservational
studies Clinical
Trials
Celecoxib (oral) ↓ ↓ mixed ↓ in subset
Statin No No No N/A
Vitamin D3 ↓↓ ↓↓ ↓ Biomarker study
Hh Antagonist (Genentech)
↓↓↓ ↓↓↓↓ none Enrolling RCT
Itraconazole (antifungal)
↓↓ ↓↓ none Biomarker study
Summary of chemopreventive agents against BCCs
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Genetic deletion of Cox1 or Cox2 decreases microscopic BCCs in Ptch1+/- mice
IR-treated Ptch1+/- mice wild type (n=24), deleted for Cox1 (n=12) or for Cox2 (n=6). Mean and SEM. p<0.05
Cox1 and Cox 2 KO: Smithies Cell 1995*
*
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Cox WT Cox1 KO Cox2 KO
BC
C B
urde
n (m
m2)
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0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
Control Celecoxib240
Celecoxib480
Celecoxib1600
BC
C b
urd
en
(m
m2
)Celecoxib decreases microscropic BCC burden in
Ptch1+/- mice (p<0.05)
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• Study design: Phase II randomized, double-blinded, placebo controlled trial
• Subjects: 60 patients with Basal Cell Nevus Syndrome (BCNS)
• Treatment: oral Celecoxib at 200mg BID versus placebo for 24 months followed by 12 months of observation
• Primary endpoint: change in BCC numbers during study periods
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Baseline characteristics of study participants are similar in two groups (mean and SD)
Placebo(N=27)
Celecoxib(N=33)
Age 42 ± 12 47 ± 12
Number of BCC tumors greater than 3mm 24 ± 27 45 ± 76
Body Mass Index 31 ± 1.3 30 ± 1.1
% Male 48% 58%
% Caucasian 96% 100%
% With >15 BCCs at baseline 41% 39%
% Seen at California site 59% 55%
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BCNS subject with low number of BCCs at baseline (<15 tumors)
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BCNS subject with high number of BCCs at baseline (>15 tumors)
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How to analyze BCC development
• Regession technique: Linear mixed models
• Calcuates a slope or rate (number of BCCs/yr) for each patient
• Compare percent change in rate of BCCs in placebo and celecoxib groups
• Accounts for drop-outs
• Adjust for age, gender, BCC at baseline
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050
010
0015
000
500
1000
1500
050
010
0015
000
500
1000
1500
180 200 220 240 180 200 220 240 180 200 220 240
180 200 220 240 180 200 220 240
3254 3282 3292 3309 3310
3313 3314 3321 3323 3329
3330 3347 3350 3352 3353
3354 3362
tum
or
daysGraphs by mouse
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Celecoxib reduces BCC development in subjects with less severe disease (< 15 BCCs)
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Lessons learned: importance of finding a reliable mouse model
• Ptch1+/- mice are a reliable model for testing new anti-BCC agents in humans– Moderate effect of celecoxib on BCCs in mice
and in BCNS patients– Greater effect on tumor size rather than
number in both mice and BCNS patients
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Lessons learned: statistics• Statistics – linear mixed models for
determining slope of BCCs in RCT• Regression models for tumors in mice
– Go to class
• Building a database (and managing)– Go to class
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Lessons learned:• Long time to publication• Journals and co-authors disagree on
whether to present data from mice and clinical trial study together
• Cancer Prevention Research
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In vitro MiceObservational
studies Clinical
Trials
Celecoxib (oral) ↓ ↓ mixed ↓ in subset
Statin No No No N/A
Vitamin D3 ↓↓ ↓↓ ↓ Biomarker study
Hh Antagonist (Genentech)
↓↓↓ ↓↓↓↓ none Enrolling RCT
Itraconazole (antifungal)
↓↓ ↓↓ none Biomarker study
Summary of chemopreventive agents against BCCs
![Page 28: Lessons Learned in T1 Research: mouse to human Jean Y. Tang MD PhD Assistant Professor Department of Dermatology.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649d415503460f94a1c433/html5/thumbnails/28.jpg)
Cyclopamine
Smo
Gli
New and relatively safe agents that decrease Hedgehog signaling
Corcoran and Scott, Proceedings of the Natl Acad Sci 2006Bijlsma and Peppelenbosch, PLOS Biology 2007
Vitamin D3, Statins
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Mechanism of disease
In vitro experiments
Animal models
Human clinical trials
Statins blocks Hedgehog pathway
BCC cell lines
Ptch1 +/- mice
Epidemiological studiesStatin therapy and risk of
subsequent BCCs in Kaiser cohort
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7dehydrocholesterol →→ Vitamin D3
Skin
Liver
Vit D3
25(OH)D
Kidney
1,25(OH)2D
Vitamin D Receptor (VDR)
24OHase
Excretion
Diet
Figure 4B2.3. Synthesis and metabolism of vitamin D3
7dehydrocholesterol →→ Vitamin D3
Skin
Liver
Vit D3
25(OH)D
Kidney
1,25(OH)2D
Vitamin D Receptor (VDR)
24OHase
Excretion
Diet
7dehydrocholesterol →→ Vitamin D3
Skin
Liver
Vit D3
25(OH)D
Kidney
1,25(OH)2D
Vitamin D Receptor (VDR)
24OHase
Excretion
Diet
Figure 4B2.3. Synthesis and metabolism of vitamin D3
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Lessons learned
• Have a good biomarker or target gene (Gli1 mRNA)
• Have a good way to measure bioavailability (24OHase)
• Have a reliable cell line
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Vitamin D3 decreases Gli mRNA in BCC cells
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Vitamin D3 and 1,25(OH)2 D activate the Vitamin D receptor
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(A) Ptch1+/- K14-Cre-ER2 p53 fl/fl mice treated with vehicle control (Left) versus topical vitamin D3 (right) at 7 months of age.
(B) Example of large BCC tumor on the dorsal skin these transgenic mice(C) Histological confirmation of BCC.
Topical Vitamin D3 decrease BCC development by 50% (p<0.05)
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Unadjusted p value Adjusted* p value
Vitamin D3 -62% .008 -53% .042
1,25(OH)2D -36% .39 -33% .43
Statin** -58% .10 -40% .30
Topical vitamin D3 decreases BCC development in mice
*Adjusted for gender and coat color of mouse
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Lessons learned
• Have a good biomarker or target gene (Gli1 mRNA)
• Have a good way to measure bioavailability (24OHase)
• Pilot trial of topical and oral vitamin D on human BCC
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Mechanism of disease
In vitro experiments
Animal models
Human clinical trials
Vit D3 blocks Hedgehog pathway
BCC cell lines
Ptch1 +/- mice
PTCH1+/- Basal cell nevus syndrome patients
Epidemiological studies Vit D3 levels in BCC pts
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Lesson Learned
• Translating from mouse studies to epidemiologic studies (skip the human clinical trial/pilot)
• Mouse to Epi (Ralph Gonzalez)
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The association of serum vitamin D with skin cancer risk in elderly men
Jean Y. Tang1,3, Neeta Parimi2, Angela Wu1,3, John Boscardin1, Meg Chren1,Steven R. Cummings1,2,
Ervin Epstein3, and Douglas C. Bauer1,2 1 University of California San Francisco, 2 San Francisco Coordinating
Center, California Pacific Medical Center Research Institute, 3
Children’s Hospital Oakland Research Institute
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Table 3 Association of increasing serum 25(OH)D levels with non- melanoma skin cancer
* Adjusted for age (continuous variable), BMI (continuous variable), season of blood draw, and clinic site † Adjusted for age, BMI, season of blood draw, clinic site, outdoor walking activity (continuous variable), and cigarette smoking (yes/no)
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In vitro MiceObservational
studies Clinical
Trials
Celecoxib (oral) ↓ ↓ mixed ↓ in subset
Statin No No No N/A
Vitamin D3 ↓↓ ↓↓ ↓ Biomarker study
Hh Antagonist (Genentech)
↓↓↓ ↓↓↓↓ none Enrolling RCT
Itraconazole (antifungal)
↓↓ ↓↓ none Biomarker study
Summary of chemopreventive agents against BCCs
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Cyclopamine
Smo
Gli
Williams and Wang , Proceedings of the Natl Acad Sci 2003
Topical Cur-414 creamOral Hh antag
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Placebo cream does not reduce BCC tumors
Day 0 Day 20 Day 35
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Untreated BCC
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Topical Hh Antagonist BCCs decreases BCC tumors
Day 0
Day 35Day 20
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Hh Antagonist cream Placebo
Tu
Hh Antagonist cream decreases Gli1 mRNA in BCC tumors
Lesson: benefits of collaborator
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Lesson: Benefits of UCSF Cancer Center core labs
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Topical Cur-414 treated BCC
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Lessons learned: mechanism of disease
1.Topical and oral HH antagonists significantly reduce murine BCCs by decreasing tumor proliferation and/or inducing follicular differentiation.
2.We know how to collect tumors, do these assays, get to mechanism of disease in future trials
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Investigator sponsored trial in BCC prevention
• Genentech Hh antagonist GDC 0449: 150mg daily
• Phase II, placebo controlled RCT in 41 Basal Cell Nevus Syndrome subjects
• Primary endpoint: change in BCCs at 12 mo and 18 mo
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Cyclopamine
Smo
Gli
New and relatively safe agents that decrease Hedgehog signaling
J Kim and P Beachy, Stanford
Itraconazole
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Mechanism of disease
In vitro experiments
Animal models
Human clinical trials
Small molecule library screen for inhibitors of
Hedgehog pathway
Cell based assays
Ptch1 +/- mice
Patients with sporadic BCCs
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Day 0, BCC A: 10mm
Day 4 – irritation and necrosis, 11 mm
Day 11 – residual BCC, 3mm
Itraconazole#178
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Cyclodextrin#5460
Day 0 – BCC B (11 mm), BCC D (10 mm), BCC G (9mm)
Day 7 – BCC B (11 mm), BCC D (10 mm), BCC G (9mm)
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Lessons learned:
• Collaboration with another basic lab – Post-doc fellows who are experts at specific
assays (5 years) vs training someone new
• Focus on getting the first pilot clinical trial of itraconazole on human BCCs– Measure Gli1mRNA in BCCs– Measure Ki67– Paired t-test (at biopsy and at excision)
• New opportunities/markets
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Lessons learned:
• Easier to translate FDA approved drug or a drug manufactured and tested by Pharma - already have paid the $$$
• New agent (vitamin D) – investigator pays– Efficacy– Stability– GMP grade for human – IND
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Challenge Lesson Learned
Celecoxib (oral) Combining mouse and RCT Statistics, finding the experts
StatinsDifficulty in combining mouse and epidemiologic results (Kaiser)
OK to disagree
Vitamin D3Difficulty of doing it all yourself: lab, mouse, pilot clinical trial
-1°Mentor and his lab -SFCC, EpiBio mentors
-Public databases
Hh Antagonist Collaborations with Genentech-Good to have lab skills
-RCT design
Itraconazole Collaborations with basic lab
FDA approved drug
-Nice to collaborate
-Time to start the pilot trial
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Children’s Hospital OaklandErvin EpsteinPo Lin SoTony Zheng XiaoElana ShpallAngela WuKris ChangYefim Khaimsky
UCSF EpiBiostatCharles McCulloch Ralph Gonzalez Steve HulleySteve CummingsDoug BauerNeeta ParimiJohn BoscardinMichael Kohn
Kaiser Division of ResearchMaryam Asgari
GenentechFred de SauvageTracy TangChris Callahan
UCSF DermMeg ChrenDan BikleLoretta Chan
Funding SourcesNRCC – CTSA KL2NIAMS – K23Prevent Cancer FoundationAmerican Skin Association