Surge gery y Resear search ch Con Conference Novel el Inhib - - PowerPoint PPT Presentation

▶
surge gery y resear search ch con conference
SMART_READER_LITE
LIVE PREVIEW

Surge gery y Resear search ch Con Conference Novel el Inhib - - PowerPoint PPT Presentation

Aug 01, 2023 647 likes •1.26k views

Surge gery y Resear search ch Con Conference Novel el Inhib ibit itio ion Strat ategie gies s for Panc ncre reatic Canc ncer r using ng Mice To receive 1.0 credit for this session, text the SMS code: NARHA HAL to 414-206-1776.

slide-1
SLIDE 1

Surge gery y Resear search ch Con Conference

Novel el Inhib ibit itio ion Strat ategie gies s for Panc ncre reatic Canc ncer r using ng Mice

ACCME A Accre reditation

  • n S

Statement: : The Medical College of Wisconsin is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for

  • physicians. AMA Cr

Credi dit D Desig ignation St Stat atement: The Medical College of Wisconsin designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Hours o

  • f Partic

icip ipat atio ion f for Alli lied H Health C h Care P Professionals ls: : The Medical College of Wisconsin designates this activity for up to 1.0 hours of participation for continuing education for allied health professionals.

To receive 1.0 credit for this session, text the SMS code: NARHA

HAL

to 414-206-1776. This code will expire in 5 days

slide-2
SLIDE 2

DEPARTMENT O OF SURGERY Division

  • n o
  • f R

Research

Research ch H Hig ighlig ights

slide-3
SLIDE 3

DEPARTMENT O OF SURGERY Division

  • n o
  • f R

Research

slide-4
SLIDE 4

DEPARTMENT O OF SURGERY Division

  • n o
  • f R

Research

2019-2020 Collaborative for Healthcare Delivery Science (CHDS) fellowship: The fellowship is one component of the educational arm of CHDS, which seeks to provide an instructional framework for trainees interested in projects that improve safety, quality, or patient experience, and that will improve patient outcomes for the same or lower costs.

Congratulations Erin Strong, MD, MBA, MPH! Research Resident, General Surgery

  • Erin

in St Strong: : The R Rothman I n Index & physician uti n utilization o n of early clinical warni ning ng s systems ( (Gene neral S Sur urgery)

  • David Vyles: Penicillin Allergy and the Effect on the CHW

Health System (Emergency Medicine)

slide-5
SLIDE 5

DEPARTMENT O OF SURGERY Division

  • n o
  • f R

Research

Office e of Resea earch AHW Limi mited d Needs eeds Fundi ding g Re Request

Awar ard S d Summar ary: to enable or augment research studies requiring additional resources to support the work, equipment purchases include lab equipment, scientific instruments, software purchases and specialty reagents. Priority will be given to projects that fit within the focus areas of the AHW funded award, Impro rovi ving H Heart H Healt lth, S h, Suppor

  • rting H

Healt lthy Min inds, a and D d Dis isman antling Can Cancer Maximu mum A Awa ward: $30,000 Awar ard Pe d Perio iod: d: 18 months Application Due in REDCap: October 1st at 5pm Notification of Award: November 15th Project Start Date: December 2nd Contact: Lizzy Schneidler Awar ard S d Summar ary: The award provides financial support for formalized, faculty-defined projects over a concentrated period of time which benefit both the faculty member and MCW Spo ponso sor: Faculty Affairs Workshop hop D Date: : Tuesday, November 5th Time: : 8-9 am Locat atio ion: HUB A1520 Applic icat atio ion D Due D Date: Friday, January 10th Co Contact: Kimara Ellefson, Associate VP Talent Strategy and Faculty Affairs

2020-21 F Fac aculty Vit ital alit ity A Awar ard Wo Workshop

slide-6
SLIDE 6

Pu Publicat ations

August 2 2019

Surgical Oncology

When to Intervene for Subclinical Cushing's Syndrome. The Surgical Clinics of North America. Hsieh LB, Mackinney E, & Wang TS) Should We Be Doing Cytoreductive Surgery with HIPEC for Signet Ring Cell Appendiceal Adenocarcinoma? A Study from the US HIPEC Collaborative. Journal of Gastrointestinal Surgery. (Levinsky NC, Morris MC, Wima K, Sussman JJ, Ahmad SA, Cloyd JM, Kimbrough C, Fournier K, Lee A, Dineen S, Dessureault S, Veerapong J, Baumgartner JM, Clarke C, Zaidi MY, Staley CA, Maithel SK, Leiting J, Grotz T, Lambert L, Hendrix RJ, Ronnekleiv-Kelly S, Pokrzywa C, Raoof M, Eng OS, Johnston FM, Greer JPatel SH)

General Surgery

Buyer's remorse: what predicts post-decision dissonance after bariatric surgery? Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery. (Wallace L, Horecki EK, Helm MC, Higgins RM, Gould JC, Lak K, Kindel TL)

Pediatric Congenital Cardiac Surgery

Extracorporeal Life Support and Increased Risk of Stroke with Carotid

  • Cannulation. American Society for Artificial Internal Organs (ASAIO). (Woods,

RK)

Pediatric Surgery

Multi-institutional trial of non-operative management and surgery for uncomplicated appendicitis in children: Design and rationale. Contemporary Clinical Trials. (Gadepalli S, Helmrath MA, Leys CM, Sato TT, Lal DR, Landman MP, Kabre R, Fallat ME, Fischer BA, Cooper JN, Deans KJ, Midwest Pediatric Surgery Consortium) Non-operative management of solid organ injuries in children: An American Pediatric Surgical Association Outcomes and Evidence Based Practice Committee systematic review. Journal of Pediatric Surgery. (Lal DR, Jancelewicz T, Shelton J, Diefenbach KA, Grabowski J, Kawaguchi A, Dasgupta R, Downard C, Goldin A, Petty JK, Stylianos S, Williams R) Neural monitoring during H-type tracheoesophageal fistula division: A way to decrease recurrent laryngeal nerve injury? Journal of Pediatric

  • Surgery. Journal of Pediatric Surgery. Wright TN

(Grant C, Hirschl RB, Lal DR, Minneci PC, Fallat ME, Midwest Pediatric Surgery Consortium)

slide-7
SLIDE 7

Next M Month:

Octo tober 9 9th , 2 201 019 HRC 1 1210/1230/1250 5:00-6:00pm Viktor H Hraska, M , MD, P PhD Professor and Chief Pediatric Congenital Cardiac Department of Surgery Plea lease n note t the e ROOM C CHANGE GE

2017 We e Ca Care A e Award U d Upda pdates: Optimizing Cardiopulmonary Bypass to Support Cerebral and Somatic Perfusion During Aortic Arch Reconstruction

slide-8
SLIDE 8

Novel Inhibition Strategies for Pancreatic Cancer using Mice

CD45 αSMA EpCAM

Clin Cancer Res; 18(16); 4266–76

Macrophage Stellate Cell PDAC Cell

slide-9
SLIDE 9

Cancer TME

slide-10
SLIDE 10

Outline

  • A. Tools & Methods
  • 1. Cell Lines
  • 2. Mouse Models
  • 3. Histology & Molecular Biology
  • B. People - the TEAM and I
  • C. TGFβ Paradox: Compartment makes the difference
  • D. A New TGFβ family member & Target for PC: Activin
  • E. Therapy turned foe in a High Fat setting: PI3K Inhibition
  • F. Implications
slide-11
SLIDE 11

Tools and Methods

slide-12
SLIDE 12

Cell Lines

HPDE HPDE-Kras cells Stellate cells MiaPaCa2 BxPC3 Panc1

slide-13
SLIDE 13

Mouse Models

  • 1. a candidate gene - usually altered in human cancer

mt Kras, mt p53, Smad4, p16 loss

2.

a gene switch (promoter) that can target specific cell types Elastase (EL), Pdx1, p48

3.

ability to genetically manipulate in order to insert the gene transgenesis, targeted manipulation, Tools & Switches

slide-14
SLIDE 14

Transgenesis: EL-Kras

1 4B 3 2

112 bp 180 bp 160 bp 115 bp

human KRASG12D

EL hGH

5’ MT hss 3’ MT hss

mutation

polyA

slide-15
SLIDE 15

ES Cell Manipulation

Gene Targeting Technology for Knockout/Knockin Mice

slide-16
SLIDE 16

PanINs human mus Cystic Neoplasms

EL-KRASG12D

Cancer Res. 2003 May 1;63(9):2016-9

Mouse Pancreatic Lesions Resemble Human

slide-17
SLIDE 17

PanINs

Cancer Cell. 2003 Dec;4(6):437-50

Pdx1-Cre/LSL-Kras (KC)

human mus PDAC

Pdx1-Cre/LSL-Kras/p53R172H (KPC)

Cancer Cell. 2005 May;7(5):469-83

Mouse Pancreatic Lesions Resemble Human

slide-18
SLIDE 18

PanINs

Mouse vs. Human

Cancer Cell. 2003 Dec;4(6):437-50

Pdx1-Cre/LSL-Kras

Cystic Neoplasms

Cancer Res. 2003 May 1;63(9):2016-9

EL-Kras

human mus

slide-19
SLIDE 19

Histology & Molecular Biology

  • A. Gross & Microscopic Pathology
  • 1. Tissue histology (pancreas, liver, GI tract, spleen)
  • 2. Cell culture (cytospin and/or grown on chamber slides)
  • 3. IHC/IF staining of proteins (biomarkers) & localization
  • 4. Lesion and stain scoring
  • B. Protein Quantitation: Western blot analyses
  • C. Cell mobility: scratch wound assay
slide-20
SLIDE 20

People: The TEAM & I

slide-21
SLIDE 21

The Investigator

slide-22
SLIDE 22

The PIMP

slide-23
SLIDE 23

TGFβ Paradox: Compartment/Timing makes the difference

slide-24
SLIDE 24
  • Science. 2008 Sep 26;321(5897):1801-6.

Common Alterations in PC

TGFβ Paradox

slide-25
SLIDE 25
  • Nature. 2016 Mar 3;531(7592):47-52.

TGFβ & Kras in PC Subtypes

TGFβ Paradox

slide-26
SLIDE 26

TGFβ Paradox

Biochem Soc Trans. 2016 Oct 15;44(5):1441-1454

slide-27
SLIDE 27

Brian DeCant

  • Dr. Morgan Barron

Kevin Adrian

  • Dr. David Bentrem

Danny Principe Emman Mascariñas

  • Dr. Boris Pasche
  • Dr. Barbara Jung

The Research Team Then

TGFβ Paradox Team

slide-28
SLIDE 28

What are the roles of TGFβ signals during the development of pancreatic neoplasms? How do TGFβ and Kras signals interact and are there differences depending on cancer state?

TGFβ Paradox

slide-29
SLIDE 29

Penetrance, Frequency, and Size of CPN lesions

EL-Kras/ Tgfbr1+/ - have less lesions vs. EL-Kras

TGFβ Paradox

Cancer Res. 2009 Dec 15;69(24):9169-74

slide-30
SLIDE 30

What we do know about TGFβ signals in PC

  • 1. enforce immunosuppression to protect pancreatic tumor cells
  • 2. promote EMT and the expansion of the TME

TGFβ Paradox

slide-31
SLIDE 31

EL-Kras EL-Kras/Tgfbr2 H&E Trichrome EL-Kras/Tgfbr1 EL-Kras altered TGFβ signals

+

TGFβ Paradox

slide-32
SLIDE 32

Granzyme B Cleaved Caspase-3 EL-Kras EL-Kras/Tgfbr2 EL-Kras/Tgfbr1 Tgfbr1+/ - may increase T-cell Cytotoxicity

TGFβ Paradox

slide-33
SLIDE 33

CD3/FoxP3 CD8 EL-Kras EL-Kras/Tgfbr2 EL-Kras/Tgfbr1 TGFβ signals support Treg cell function

TGFβ Paradox

slide-34
SLIDE 34

PCNA Granzyme B EL-Kras EL-Kras/Tgfbr1 Tgfbr1+/ - increases T-cell Cytotoxicity

TGFβ Paradox

slide-35
SLIDE 35

CD3/Ecad CD8 CK19/GrzB Caspase3 KC-ATwt KC-ATTgfbr1+/- KC-ATwt KC-ATTgfbr1+/- Adoptive Transfer of TGFBR1-Deficient CTLs

TGFβ Paradox

Cancer Res. 2016 May 1;76(9):2525-39

slide-36
SLIDE 36

Immune Interface Checkpoints

TGFβ Paradox

slide-37
SLIDE 37

Body Weight (g)

5 10 15 25 30 20

KPC +Invivomab (PD-1) +Galunisertib (TGFBR1)

*

KPC - vehicle KPC – Gal + Inviv

Preclincal Assessment: TGFBR1 & PD-1 Inhibition

TGFβ Paradox

slide-38
SLIDE 38

Preclincal Assessment: TGFBR1 & PD-1 Inhibition

TGFβ Paradox

Mol Cancer Ther. 2019 Mar;18(3):613-620

slide-39
SLIDE 39
  • Oncogene. 2017 Jul 27;36(30):4336-4348

TGFβ Paradox

slide-40
SLIDE 40

A New TGFβ family member & Target for PC: Activin

slide-41
SLIDE 41

modified from Front Mol Neurosci. 2016 May 10;9:32. doi: 10.3389

New Target: Activin

slide-42
SLIDE 42

The Research Team Now (sort of)

Jonas Georgi Carolina Karla

New Target: Activin

slide-43
SLIDE 43

KC

X

Acvr1a CA Acvr1a fl/fl KC Acvr1a CA KPC/Acvr1afl/fl

X

Building Acvr1a Mouse Models

KPC

New Target: Activin

slide-44
SLIDE 44

Loss of Acvr1a in PC Mice improves survival

Control Pancreas Anti-Activin Ab Liver Liver (CK19)

New Target: Activin

slide-45
SLIDE 45

Loss of Alk2 in KPC mice delays metastasis

KPCA-/- KPC 5 months of age

New Target: Activin

slide-46
SLIDE 46

PBS

% Wound Coverage PBS PBS PBS Activin Activin Activin ACVR1A WT ACVR1A CA ACVR1A KD

Acvr1a WT

PBS Activin 0 hr 24 hr 72 hr

Acvr1a CA

PBS Activin

Expression of Acvr1a-CA increases migration

New Target: Activin

slide-47
SLIDE 47

Expression of Acvr1a-CA in KC mice

Control (6mo.)

New Target: Activin

slide-48
SLIDE 48

Oncogene 2017 Jul 27;36(30):4336-4348

SNAIL Vimentin Control Act signal Block Β-Actin Total AKT pAKT

Differences between Activin & TGFβ regarding AKT

TGFβ signals - appear to work through pERK Activin signals - appear to work through pAKT Activation of AKT via phosphorylation is worth considering

PI3K could be a reasonable Target

New Target: Activin

slide-49
SLIDE 49

p110γ Normal Patient 1 Patient 2 Normal Mean p110γ score PDAC

PI3Kγ is overexpressed in human PC

Another Target: PI3Kγ

slide-50
SLIDE 50

KC

X

PI3Kγ CA PI3Kγ KO KC PI3KγCA KC PI3Kγ-/-

X

Building PI3Kγ Mouse Models

KC

Another Target: PI3Kγ

slide-51
SLIDE 51

B6 KC KPC p110γ B6 KC KPC Mean p110γ score

PI3Kγ is overexpressed in mouse PC

Another Target: PI3Kγ

slide-52
SLIDE 52

KC H&E pAKT PCNA/CK19 KC-PI3Kγ-/-

PCNA+Cells/40xField

Loss of PI3Kγ reduces pAKT & disease burden

KC KC-PI3Kγ-/- KC KC-PI3Kγ-/- Lesion Frequency

Another Target: PI3Kγ

slide-53
SLIDE 53

High Fat Diet blocks effects of PI3Kγ loss

KC H&E pAKT PCNA/CK19 KC-PI3Kγ-/-

KC KC-PI3Kγ-/- KC KC-PI3Kγ-/- PCNA+Cells/40xField Lesion Frequency

Another Target: PI3Kγ

slide-54
SLIDE 54

KC KC-PI3Kγ-/- Chow HFD

KC-PI3Kγ mice develop severe steatosis

KC KC-PI3Kγ-/- KC KC-PI3Kγ-/- Steatosis Score Serum (NEFA)

Another Target: PI3Kγ

slide-55
SLIDE 55

p110α

Fold Change

1 2 3 4 5 6 7

**

C D

  • D

1 2 3 4 5 6 7

** ** **

p110β

Fold Change

PI3Kγ associates with increased expression of PI3Kα & β

KC KC-PI3Kγ-/- KC KC-PI3Kγ-/-

  • PNAS. 2019 Jul 16;116(29):14724-14733.

Another Target: PI3Kγ

slide-56
SLIDE 56

Implications

  • Where genes/oncogenes are altered matters: epithelial vs. mesenchymal
  • Non-epithelial TGFβ signals are more sinister by suppressing immune support
  • New treatements are likely when considering novel targets
  • Activin and/or its receptors may serve as points of therapy for improved survival
  • Combined therapies have potential benefits
  • TGFβ and Activin may work well in conjunction with PD-1/PD-L1 dual targeting
  • Beware of Complications/Toxicity due to metabolic imbalance(s)
  • Fatty Liver Disease may indeed impact cancer therapies
slide-57
SLIDE 57

Funding Sources

H-Foundation Bridge (NU) Internal Support – DOM (UIC)

Main Collaborators

  • Dr. Barbara Jung
  • Dr. HG Munshi (NU)
  • Dr. David Bentrem (NU)

EL-Kras/TGFβ Project

  • Dr. Boris Pasche (Wake-Forest)
  • Dr. Qinghua Zeng
  • Dr. Mike Pennison
  • Dr. Laurent Bartholin (INSERM)

Acknowledgements

Lab Investigators

Georgina Mancinelli Karla Castellanos Ronald McKinney

  • Dr. Carolina Perales-Torres
  • Dr. Steve Waters

Danny Principe Andrew Diaz Emman Mascarinas Morgan Barron Kevin Adrian Akilesh Honosage Brian DeCant

  • Dr. Michelle Schultz
slide-58
SLIDE 58

Be Bold . . . and Take the Cat by the Ears

slide-59
SLIDE 59