Tuesdays, 12 noon, Holden AuditoriumAll students,Postdocs, faculty, staff welcome

Schedule for 2014 CourseJan 21 Ratner Introduction Jan 28 Ravi Salgia Novel targets in lung cancerFeb 4 Shaw - BRAFFeb 11 Wartman – personalized medicineFeb 18 Romee-NK therapyFeb 25 Charles Rudin – Lung treatments Mar 4 Obi Griffith-druggable genomeMar 11 Sleckman - DNA repair Mar 18 Bose – HER 2Mar 25 Frederick Appelbaum-AMLApr 1 Uy – bispecific antibodiesApr 8 Lim Cell signaling in lymphomaApr 15 Pearse –T cell metabolism in cancer Apr 22 ? Guest LecturerAttendance of all sessions & active discussion esp during presentation classic paper

WebSite: http:siteman.wustl.edu/physicianh/prof.education_onlineFormat: 45-55 min didactic/30 min discussion

1.6 million new cases this year21% decrease in cancer-related deaths

in men vs 1990s12% decline in women

13 million cancer survivors alive in USCancer-related death rates decline

1.5%/yr580,000 Americans died of cancer in

2013

IntroductionHistoryPrinciples of Cancer BiologyAdvances in TreatmentAdvances in PreventionCurrent Social IssuesSee Perspectives in Nature Reviews in

Cancer JCO Jan 2014, Clinical Cancer Advances

deVita NEJM 2012 History of Cancer Hanahan & Weinberg Cell, 2011

1600 BC Egyptian physician record 1st description of breast cancer

460 BC Hippocrates uses “carcinos” to describe tumors (Greek – crab)

129 AD Galen attributes cancer to black bile

1660 Mastectomy for breast cancer

1713 Ramazzini noted lack of cervical ca but increased breast ca in nuns

1775 Pott describes scrotal cancer in chimney sweeps

1838 Muller describes cancer as abnormalities of cells

Cell-cycle checkpoints (Hemmungseinrichtung: inhibitory mechanism) that would allow cell division only when a specific

external stimulus is experienced by the cell.

The clonal origin of tumours.

. Tumour-suppressor genes (Teilungshemmende Chromosomen), the effects of which can be overcome by external signals, and which are

physically lost in progressively growing tumours.

Oncogenes (Teilungsfoerdernde Chromosomen) that become amplified (im permanenten Übergewicht) during tumour development.

Tumour progression from benign to malignant, involving sequential changes of increased growth-stimulatory chromosomes & loss of growth-inhibitory chromosomes.

Cancer predisposition through inheritance of chromosomes (genes) that are less able to suppress malignancy.

Cancer predisposition through inheritance of genes that cause aberrant mitoses.

The role of wounding and inflammation in tumour promotion.

Loss of cell adhesion in metastasis.

Sensitivity of malignant cells to radiation therapy.

Sleckman

Pearse

• 200 adult cases• fewer mutations (13) than most other adult cancers• average of 5 are in genes that are recurrently mutated• 23 genes were significantly mutated• at least one driver in nearly all AMLs• mutation in one of 9 cate- gories of genes relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%)• Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories Wartman, Griffith, Applebaum

Targeting BTK with Ibrutinib in Relapsed

CLL & Mantle Cell Lymphoma

N Engl J Med 2013; 369:32 & 507, For CLL, at 26

mos, PFS 75%, OS 83%, For MCL PFS 13.9 mos

Lim

Ponatinib in Refractory CMLN Engl J Med 2012; 367:2075-2088

Patients who had chronic-phase CML with the T315I mutation, 100% had a CR

Blinatumomab in patients with MRD in B-lineage ALL

Blood 2012 120:5185-5187bispecific single-chain (BiTE)

Abs, engages T cells for redirected lysis of CD19+ target

cellsALL patients with persistent or relapsed MRD, 80% MRD RR

Uy

Drug Approvals 2012-3, Heme MalignanciesNewly ApprovedCarfilzomib Progressive myeloma

Pomalidomide For relapsed/refractory myeloma

Omacetaxine mepesuccinate

Accelerated phase CML

Ponatinib CML or PH-pos ALL resistant to prior TKI

Expanded Indications

Vincristine liposome

Relapsed ALL

Lenalidomide Mantle cell lymphoma

Romee

Newly ApprovedPertuzumab For HER2+ with trastuzumab

+ docetaxel

Trastuzumab-DM1

For HER2+ metastatic breast cancer

Expanded Indication

Everolimus ER+ breast cancer with exemestane

Drug Approvals 2012-3, Breast Cancer

Bose

• Impairs xenograft growth• Promotes astroglial differen-tiation• Inhibits histone methylation

The Lancet, Volume 381, Pages 303 - 312, 26 January 2013 Regorafenib, Multifunctional inhibitor against VEGFR-2 & TIE2

OS 6·4 months in the regorafenib group vs 5·0 months in the placebo group

Nature Volume: 486, Pages: 532–536 (28 June 2012)KRASm detectable in blood as early as 10 months before disease

progression. Early initiation of a MEK inhibitor as a strategy for delaying or reversing

drug resistance

Nature Volume: 483, Pages: 100–103 (01 March 2012)BRAF(V600E) inhibition causes feedback activation of EGFR

Melanoma cells express low levels of EGFR and not subject to feedback

activation.Might benefit from combination therapy consisting of BRAF and EGFR

inhibitors* TCGA-WNT/bCAT, RAS, PI3K, 2nd line BEV, CET adj not beneficial, ziv-

aflibercept

Shaw

Newly ApprovedZiv-aflibercept Resistant colorectal cancer

with FOLFIRI

Regorafenib Progressive colorectal cancer

Expanded Indication

Cetuximab 1st line KRASwt colorectal cancer

Drug Approvals 2012-3, Colorectal Cancer

Enzalutamide (MDV3100): N Engl J Med 2012; 367:1187 AR antagonist, 5x binding affinity vs bicalutamide, blocks nuclear

translocation & coactivator binding, OS 18.4 vs 13.6 months in placebo group

Abiraterone (17-OHase, C17:20-lyase) N Engl J Med 2013; 368:138PFS 16.5 months with abiraterone–prednisone and 8.3 months with

prednisone

Radium 223 (α emitter) N Engl J Med 2013; 369:213OS 14.0 mos vs 11.2 mos with placebo

2 protons/2 neutrons, T1/2 = 11d, bone-seeking

Cabozantinib, JCO 2013; 31:41272% regression in soft tissue lesions,

68% improvement on bone scan, 12% CRPFS 24 weeks vs 6 weeks with placebo

57% had ≥ 50% reduced alk phos and C-terminal telopeptide of collagen I67% improved bone pain, 56% decreased narcotic use

16% grade 3 fatigue , 12% HBP, 8% hand-foot syndrome.

Nature Genetics 2013;45:747XAF1, XIAP and SRD5A1 as a predictive and

actionable signature for CRPC.XAF1 = XIAP-associated factor

SRD5A1 = 3-oxo-5-alpha-steroid 4-dehydrogenase 1

Cell 2013; 155:1309Induction of glucocorticoid receptor expression as a common feature of drug-resistant tumors

Newly ApprovedEnzalutamide Docetaxel refractory prostate

cancer

Ra223 For bone metastases of prostate cancer

Axitinib Renal cell carcinoma

Expanded IndicationAbiraterone Castration-resistant prostate

cancer

Drug Approvals 2012-3, GU Cancers

Cabozantinib delays MTC progression Sorafenib reverses RAI resistance of DTC Panitumumab improves survival of HPV-neg squamous cell cancers Freq abnormalities in squamous cell carcinomas in FGFR1, 2, DDR2, EPHA2, PI3K pathways

Adeno-p53 plus chemotherapy increases survival in late-stage oral cancer

3 yr OS 88% vs 60%

Squamous CellNature 489: 519–525 (27

September 2012)Alterations in targetable

oncogenic pathways:FGFR, DDR2, PI3K

AdenocarcinomaCell. 2012 Sep 14;150:1121-34

EFGRm and KRASm in founder clones14 fusions, including RET, ROS1 and ALK &

novel metabolic enzymesCell-cycle and JAK-STAT pathways

altered with perturbations in 54 genes that may be targetable with available drugs

Salgia, Rudin

Melanoma - Anti–PD-1 Antibody N Engl J Med 2012; 366:2443-2454

RR 28% Melanoma ,27% Renal, 18% NSCLC

Additive to CTLA4 blockade

PTCHm, Vismodegib – SMOi, fatigue

Weight loss, dysgeusia, m spasms

ANG,CYCD1,Anti-apoptosis

Newly ApprovedVismodegib Advanced basal cell ca

Dabrafenib, Trametinib

BRAFm metastatic melanoma

Drug Approvals 2012-3, Skin Cancers

Pazopanib for refractory soft tissue sarcoma

Lancet 379:1879-1886, May 2012

OS 12·5 mos with pazopanib vs 10·7 months

multitargeted tyrosine kinase inhibitor, with activity against

VEGFR1,2,3 & PDGFR

PD0332991 in Patients With Advanced CDK4-

Amplified Well-Differentiated or Dedifferentiated

Liposarcoma JCO 2013 31:2024-2028

CDK4 is amplified in > 90% of well-differentiated (WDLS)

and dedifferentiated liposarcomas (DDLS); PFS 18

weeks, 1 PR

Regorafenib for refractory GIST

Lancet 381:295-302, 2013

PFS was 4·8 months for regorafenib and 0·9 months

for placebo

Circulating DNA instead of bx

Expanded IndicationsImatinib Adjuvant GIST

Regorafenib Treatment-resistant GIST

Pazopanib Advanced soft tissue sarcoma

Denosumab For giant cell bone tumor

Drug Approvals 2012-3, Sarcomas

Low-Dose CT Screening for Lung Cancer (NEJM 2013)

A total of 53,439 eligible participants were randomly assigned to a study group (26,715 to low-dose CT and 26,724 to chest radiography)

Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants)

Sensitivity and specificity were 93.8% and 73.4% for low-dose CT and 73.5% and 91.3% for chest radiography, respectively.

• Number of new grants at lowest level since 1998• If sequester not reversed, budget cuts will continue until 2021• LOBBY CONGRESS

• NIH cut existing grants by 10%• Eliminated 700 viable projects that would otherwise have been considered• NIH budget declined 22% over last decade

Drug ShortagesNotify FDA re drug withdrawals

Economic incentives

Emphasis on Quality and Value in Cancer Care

Therapy only for pts who will benefitAvoid imaging/biomarkers in early stage

prostate & breast caAvoid CSFs if <20% likelihood of febrile

neutropenia

Continued progress depends on access to clinical trials and quality care

Faster and smarter clinical trials utilizing information technology

Revitalize federal funding of clinical trials Examine potential impact of health care

reform on cancer disparities Assist FDA in addressing cancer drug

shortages Improve advanced cancer care planning

Highlight potential solutions for oncology workforce shortages

Assist UN in addressing cancer crisis in developing counties