Renal cell carcinoma rcc molecular basis of therapeutic approaches
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Renal Cell Carcinoma (RCC): Molecular Basis of Therapeutic Approaches. Moderator Michael A. Carducci, MD Professor of Oncology and Urology Johns Hopkins Medical Institutions Baltimore, Maryland Faculty William G. Kaelin Jr., MD Professor of Medicine

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Renal Cell Carcinoma (RCC): Molecular Basis of Therapeutic Approaches

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Renal cell carcinoma rcc molecular basis of therapeutic approaches

Renal Cell Carcinoma (RCC): Molecular Basis of Therapeutic Approaches

Moderator

Michael A. Carducci, MD

Professor of Oncology and UrologyJohns Hopkins Medical InstitutionsBaltimore, Maryland

Faculty William G. Kaelin Jr., MD

Professor of Medicine

Harvard Medical SchoolDana-Farber Cancer Institute Boston, Massachusetts

Hans-Joerg Hammers, MD, PhD

Assistant Professor of Urologic Oncology

Johns Hopkins Medical InstitutionsBaltimore, Maryland


Overall goal

Overall Goal

The goal of this educational activity is to review the molecular pathways for choosing therapies based on the molecular biology of kidney cancer


Role of vhl gene in rcc

Role of VHL Gene in RCC

  • Inactivation of the VHL tumor-suppressor protein

  • Accumulation of HIF transcription factor

  • Overexpression of a number of genes, including VEGF

VHL = von Hippel Lindau; HIF = hypoxia-inducible factor; RCC = renal cell cancer; VEGF = vascular endothelial growth factor


Review of published literature vhl gene inactivation

Review of Published Literature - VHL Gene Inactivation

aGnarra JR, et al.Nat Genet. 1994;7:85-90. bShuin T, et al. Cancer Res. 1994;54:2852-2855.

cGallou C, et al. Hum Mutat. 1999;13:464-475. dSchraml P, et al. J Pathol. 2002;196:186-193.

eYao M, et al. J Natl Cancer Inst. 2002;94:1569-75. fvan Houwelingen KP, et al. BMC Cancer. 2005;5:57.


Vegf and mtor inhibitors

VEGF and mTOR Inhibitors

  • VEGF inhibitors

  • Bevacizumab – Neutralizing antibody against VEGF

  • Sunitinib

  • Sorefenib Small molecules inhibitors

  • Pazopanib against the VEGF receptor, KDR (VEGF-R2)

  • mTOR kinase inhibitors

  • Temsirolimus

  • Everolimus

KDR = kinase domain receptor; mTOR = mammalian target of rapamycin


Vegf correlated with poorer overall survival

VEGF Correlated With Poorer Overall Survival

Jacobsen J, et al. BJU Int. 2004;93:297-302.


Vegf signaling mechanisms

VEGF Signaling Mechanisms

Antibodies to VEGF

or VEGFR

mTOR

inhibitors

Tyrosine kinase inhibitors

Erk = extracellularly regulated kinase; MAPK = mitogen-activated protein kinase; MEK = MAP/Erk kinase; PKB = protein kinase B; VEGFR = VEGF receptor

Adapted from Rini BI, et al. J Clin Oncol. 2005;23:1028-1043.


Relationships between vhl and mtor

Relationships Between VHL and mTOR

  • Direct relationship between VHL loss and increased VEGF activity

  • mTOR indirectly affects HIF and VEGF

  • Not clear which mTOR activities are relevant to kidney cancer

  • Inhibition of mTOR with rapamycin-like drugs can activate upstream kinases


Renal cell carcinoma rcc molecular basis of therapeutic approaches

Roles of VEGF and mTOR Inhibitors

Temsirolimus

Everolimus

RAPTOR

pVHL

mTOR

Transcription/Synthesis

Destruction

HIF

HIF

HIF

Cancer Cell

VEGF

Bevacizumab

Extracellular Space

KDR

Endothelial Cell

Sunitinib

Sorafenib

Pazopanib

RAPTOR

mTOR

AKT

PI3K

Temsirolimus

Everolimus

Courtesy of William G. Kaelin Jr., MD


Effectiveness of current therapies

Effectiveness of Current Therapies

  • VEGF inhibitors as monotherapy are not curative

  • Combination therapies

    • Must have different mechanisms of action

    • Should not be cross-resistant

    • Ongoing clinical trials address

    • VEGF inhibitors with mTOR inhibitors

    • Bevacizumab, sorafenib, and temsirolimus in patients with metastatic RCC[a]

    • Everolimus and vatalanib in treating patients with advanced solid tumors[b]

    • Phase 1b, open-label, dose-finding study to evaluate the safety of tivozanib (AV-951) in combination with temsirolimus in subjects with metastatic RCC[c]

aClinicaltrials.gov. Available at: http://clinicaltrials.gov/ct/show/NCT00378703

bClinicaltrials.gov. Available at: http://clinicaltrials.gov/ct/show/NCT00303732

cClinicaltrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00563147


Questions that remain unanswered

Questions That Remain Unanswered

  • Is the combination of these agents actually adequate for all patient populations?

  • Can we stratify patients to these treatments with some patient groups benefiting more from the combinations than others?

  • What are the potential mechanisms of resistance to, for example, VEGF-based agents?

  • Will combinations with mTOR inhibitors break this resistance?


Renal cell carcinoma rcc molecular basis of therapeutic approaches

Targets: HIF-Responsive Gene Products

Pazopanib

CA = carbonic anhydrase; c-Met = mesenchymal-epithelial transition factor; CTGF = connective tissue growth factor; CXCR = CXC chemokine receptor; HDAC = histone deacetylases; MMP = matrix metalloproteinase; PDGF = platelet-derived growth factor; pVHL = VHL protein; SDF = stromal cell-derived factor; TGF = transforming growth factor

Kaelin WG Jr. Cancer. 2009;115(10 Suppl):2262-2272.


Renal cell carcinoma rcc molecular basis of therapeutic approaches

mTOR

Inhibition of TORC1 and TORC2 Complexes

Extracellular

RTK

Torc2 complex

(rapalog insensitive)

Intracellular

RICTOR

PI3K

AKT

Additional oncogenic functions

RAPTOR

Torc1 complex (rapalog sensitive)

mTOR

Temsirolimus and everolimus are rapalogs

HIF

Courtesy of William G. Kaelin Jr., MD


Renal cell carcinoma rcc molecular basis of therapeutic approaches

pVHL Activity in Physiologic and

Pathologic States

Rathmell WK, Chen S. Exp Rev Anticancer Ther. 2008;8:63-73.


Renal cell carcinoma rcc molecular basis of therapeutic approaches

Molecular Pathways and Targeted Therapies

PDGFR = PDGF receptor; PTEN = phosphatidylinositol phosphate 3'-phosphatase; FKBP = FK binding protein; TSC = tuberous sclerosis complex

Brugarolas J. N Engl J Med. 2007;356:185-187.


Renal cell carcinoma rcc molecular basis of therapeutic approaches

Responses With High-Dose IL-2

  • US Food and Drug Administration-approved high-dose IL-2

    • Durable responses in carefully selected patients

    • Toxic

    • Substituting with lower dose or adding interferon produced fewer tumor regressions

  • Predictors of response to IL-2 therapy

    • Patients with clinical features of a good or intermediate prognosis

    • Tumors with clear-cell histology

IL = interleukin

McDermott DF. Clin Cancer Res. 2007;13:716s-720s.


Immunologic agents in clinical development

Immunologic Agents in Clinical Development

  • Antibodies to CTLA4

    • Phase 2 study with iplilimumab[a]

    • Response was 4% to 27% by RECIST in IL-2 nonresponders

  • Antibodies to PD1

    • Phase 1/2 trial of MDX-1106 in solid tumors

    • Clinical activity against RCC and melanoma with intermittent dosing at 10 mg/kg

    • No serious toxicity

CTLA4 = cytotoxic T-lymphocyte-associated protein 4; RECIST = response evaluation criteria in solid tumors

aYang JC, et al. J Immunother. 2007;30:825-830.

bBrahmer JR, et al. J Clin Oncol. 2009;27(15s):3018.


Met in rcc

MET in RCC

  • MET signaling has been shown to be important in RCC[a]

  • MET can cooperate with epidermal growth factor receptor[b]

  • MET mutations drive the pathology in hereditary papillary kidney cancer[a]

  • Papillary kidney cancer is an ideal RCC tumor for the study of MET-targeted therapies[a]

  • The rational design and development of MET inhibitors has produced a number of potent and selective agents[a]

  • MET is an HIF target gene and therefore a potential target in clear-cell RCC[a]

aGiubellino A, et al. Expert Rev Anticancer Ther. 2009;9:785-793.

bInoue K, et al.Virchows Arch. 1998;433:511-515.


Met signaling pathway

MET Signaling Pathway

GRB = growth factor receptor binding protein; PLC = phospholipase C

Abounader R, et al. Oncogene. 2004;23:9173-9182.


Potential predictors of outcome

Potential Predictors of Outcome

  • Histology: Tyrosine kinase inhibitors promise longer progression-free survival in clear-cell histology

  • Clinical prognostic factors combined with histologies can help guide treatment selection in poor-risk patients

  • Poor-risk patients can also benefit from tyrosine kinase inhibitors


Waterfall plots of primary tumor responses size response to sorafenib therapy

Waterfall Plots of Primary Tumor Responses: Size Response to Sorafenib Therapy

Response evaluation criteria in solid tumors: partial response criteria designated by lower dashed line at −30% and progressive disease criteria designated by upper dashed line at 20%.

LD = longest dimension

Cowey CL, et al. J Clin Oncol. 2010;28:1502-1507.


Renal cell carcinoma rcc molecular basis of therapeutic approaches

Axitinib Treatment for Cytokine-Refractory mRCC: Phase 2 Study

Axitinib - Investigational KDR inhibitor

Maximum percentage of tumor decrease for target lesions by RECIST

Zero represents baseline (no change), -100% represents potential complete response, ~ 30% represents potential partial response

Rixe O, et al. Lancet Oncol. 2007;8:975-984.


Improving response

Improving Response?

  • Does HIF-1-alpha status affect the response to VEGF inhibitors?

  • Will the use of a pharmacodynamic biomarker (hypertension) provide more effective dosing?

  • Which VEGF inhibitor has good potential in combination therapy?


Resistance mechanisms

Resistance Mechanisms

  • IL-8 contributing to VEGF resistance[a]

  • Acquired or transient resistance[b]

aHuang D, et al. Cancer Res. 2010;70:1063-1071.

bMotzer RJ, et al. J Clin Oncol. 2009;27:3584-3590.


Toxicity of sunitinib plus bevacizumab

Toxicity of Sunitinib Plus Bevacizumab

Characteristics of patients in whom TMA developed compared with characteristics of patients with RCC

TMA = thrombotic microangiopathy; LDH = lactate dehydrogenase; HFS = hand-foot syndrome; S = sunitinib; B = bevacizumab

Rini BI, Garcia JA. J Clin Oncol. 2010;28:e284-e285.


Toxicity of sunitinib plus bevacizumab cont

Toxicity of Sunitinib Plus Bevacizumab (cont)

*Dose levels for other patients with RCC included S 25 mg/B 5 mg/kg (1 pt), S 37.5 mg/B 5 mg/kg (3 pts), S 37.5/B 10 mg/kg (1 pt), and S 50 mg/B 10 mg/kg (3 pts). † Two pts with papillary features and 1 pt with sarcomatoid features. ‡ Baseline haptoglobin and reticulocyte count not be measured in the majority of patients enrolled in initial cohort. No patient with haptoglobin < 20 on any measurement.

§ Two pts unevaluable due to lack of postbaseline scans.

Rini BI, Garcia JA. J Clin Oncol. 2010;28:e284-e285.


Adjuvant therapy for those at high risk for relapse

Adjuvant Therapy for Those at High Risk for Relapse

  • There is no evidence for benefit of adjuvant therapy in clear-cell RCC at this time

  • Should it be given before or after nephrectomy?

  • Will molecular markers be better able to identify high-risk patients?

  • Adjuvant therapy

    • Sunitinib, sorafenib, bevacizumab

    • Temsirolimus and everolimus

    • Immunotherapy with CTLA-4 and PD-1 antibodies

Bleumer I, et al. Can J Urol. 2006; Suppl 2:57-62.

Jonasch E, Tannir NM. Cancer J. 2008;14:315-319.

de Reijke TM, et al. Eur J Cancer. 2009;45:765-773.


Renal cell carcinoma rcc molecular basis of therapeutic approaches

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