Targeting Papillary

Kidney Cancer Variants

Brian Shuch, MD

Associate Professor of Urology

Director, Kidney Cancer Program

Alvin & Carrie Meinhardt Endowed Chair

in Kidney Cancer Research

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“The Genetic Basis of RCC”

Clear Cell Papillary Type 1 Papillary Type 2 Chromophobe Oncocytoma

VHL MET FLCNFH

Linehan, WM, Walther, MM, Zbar, B. The genetic basis of cancer of

the kidney. The Journal of urology (2003) 170(6 Pt 1):2163-2172.

Reminisce to Simpler Times (Pre-TCGA)

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Papillary RCC Are

Heterogenous

4Comprehensive Molecular Characterization of Papillary Renal-Cell

Carcinoma. (2015). Comprehensive Molecular Characterization of

Papillary Renal-Cell Carcinoma., 374(2), 135–145.

TCGA Expands Our Understanding of pRCC

What is recommended for “non-clear cell”

Clinical Trial Aiming to See The Standard of Care

S1500 Translational Objectives (Integrated Biomarkers)

Two integrated biomarkers are hypothesized to be both prognostic and

predictive in papillary kidney cancer patients treated with MET inhibitors.

1) Papillary subtype by central pathology review

• Type I versus Type II or NOS

2) MET Alteration Status including:

• MET mutation

• MET amplification

• MET mRNA overexpression

Ongoing Central Path Review

• Central review- 108 uploaded

• Challenging to call from 1-2

slides, immunostains, and path

report

• Poor Consensus: 36% with

complete agreement

Type 1 28

Type 2 49

Other 21

Pending Conference 10

S1500 Correlative Science

Biomarkers Approach

• Whole Exome Sequencing

• MET signaling pathway primary focus

• MET/HGF CNV changes (with confirmation via SNParray)

• Additional KIRP Genes

• Nanostring (dtRT-PCR)

• MET pathway gene set (GSEA=54)

• Exploratory aims:

-MET splice variants (seen in TCGA KIRP and other cohorts)

-MET kinase fusions (seen in various TCGA cohorts)

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S1500 Correlative Science

Exploratory MET Activation: Splicing/Fusions

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Stransky, N., Cerami, E., Schalm, S., Kim, J. L., & Lengauer, C.

(2014). The landscape of kinase fusions in cancer. Nature

Communications, 5, 4846.

• splice variant missing exons

1&2 without extracellular

ligand binding domain

• 8 tumors (~5%) found with

novel MET splice variant

• cause ligand-independent

MET signaling

• 6 chimeric proteins found in TCGA

cohorts including KIRP follows the

classic activation paradigm, fusing

dimerization motifs to an intact

kinase domain

Its Not all About MET!

• While S1500 may establish a MET inhibitor as a standard of care for pRCC, its not expected to be a home run even for MET-driven tumors

• Need to better understand new targets/therapeutic approach

• A large well-annotated data and specimen collection will allow more rapid advancement in understanding aggressive pRCC

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Validation of Prior Work with S1500 Cohort:

Whole Genome KIRP: Mutational Signatures

• Yale Team helped with Whole Genome analysis during TCGA KIRP

• Analysis not included in the NEJM paper

• Pattern of SNV may predict mechanism of tumorigenesis

• Additional work performed for signatures from WGS and WES

• ~20% with unique signature 3 “BRCAness”

• Some of these were the CIMP cohort

Li, S., Shuch, B. M., & Gerstein, M. B. (2017). Whole-genome analysis

of papillary kidney cancer finds significant noncoding alterations. PLoS

Genetics, 13(3)

Ranjit Bindra’s

Work in IDH1/2

(cholangio/glioma)

Relevant to

FH/SDH

Tumors?

UOK262 HLRCC

Model

Sulkowski, P. L., Sundaram, R. K., Oeck, S., Corso, C. D., Liu, Y.,

Noorbakhsh, S., et al. (2018). Krebs-cycle-deficient hereditary cancer

syndromes are defined by defects in homologous-recombination DNA

repair. Nat Genet, 31(8), 1578–1092.

SDH, FH, IDH1/2

Bench-to-bedside Approach

Additional Biomarker Analysis for S1500

• Reprocessing of Whole Exome Sequencing

• Mutational Signature including those with a possible HRD

• HLRCC and HLRCC-like pRCC

• Nanostring (dtRT-PCR)

• CIMP genes, HR genes, IO genes

• 500 gene classifier (TCGA signature) to molecular subclassify

• Mass Spec from Tissue

• Evaluate if linked to the CIMP/HLRCC phenotype

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Mass Spec Analysis

from FFPE

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FFPE samples from HLRCC kidney cancers

(high) and matched tumor/normal cases from

sporadic renal tumors.(less than lower limit of

quantification)

Conclusions • pRCC heterogenous disease

• Needs molecular characterization > Pathologic characterization

• MET inhibitor therapy may be a viable approach and be the standard of care but only a subset may benefit

• S1500 will allow robust correlative science to look at the MET pathway but will allow us to validate prelim work

• Some papillary variants may be HLRCC/HLRCC-like and may have an HR-Defect

• Treatment with PARP inhibitors promising, though we have only seen stable disease.

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