# Presentation: 592734

## Dr. John E. Niederhuber
Acting Director

National Cancer Advisory Board
June 14, 2006

**Dr. John E. Niederhuber**
- Acting Director
*National Cancer Advisory Board*
*June 14, 2006*

**Director’s Update**

## NCAB – Director’s Update

**Awards to intramural scientists**
**New appointments to NCI**
**Applications, Awards and Success Rates**
**Lung cancer program**
**HPV vaccine **

## U.S. Death Trends: Cancer of All Sites, 1975-2003

**Decline**** ****of**** ****-1.1%**** ****since 1994**
**Decline for**** ****men is -1.6%**** ****per year since 1993**
**Decline for**** ****women is -0.8%**** ****per year since 1992**
**Decline**** ****continues for Prostate, Breast (F), Colorectal, Lung (M), and many other sites**

## 2006 – Final Quarter

**Have been hit with a **_**mid-year increase in taps**_** for direct utility costs to NIH of almost $4 million**
**RPG **_**payline running about 11th percentile**_**; 15% of the competing pool in reserve for some exceptions**
**Type 5s generally **_**2.35% below the commitment**_** of record**
_**SPOREs are 2% below FY2005**_** and Centers are essentially flat with FY05**
**Training is 1% above the FY05 level**

## Honors

**Honors**

**Medal of Honor, International Agency for Research on Cancer**** **
**Joseph Fraumeni, M.D.**
**Director, DCEG**

**Marvin Zelen Leadership Award in Statistical Science**
**Mitchell Gail, M.D., Ph.D.**
**Chief of the Biostatistics Branch, DCEG**

**Notes:**
Dr. Joseph Fraumeni, Director of the Division of Cancer Epidemiology and Genetics received the Medal of Honor from the International Agency for Research on Cancer in recognition of his outstanding contributions to the field of cancer epidemiology.   He also delivered the 3rd Richard Doll Lecture entitled “Genes and the Environment in Cancer Causation:  An Epidemiologic Perspective.”

Marvin Zelen Leadership Award in Statistical Science presented to Dr. Mitchell Gail, Chief of the Biostatistics Branch, DCEG  received the from the Dept. of Biostatistics at the Harvard School of Public Health.  His lecture illustrated the clinical applications of a model for absolute breast cancer risk, often referred to as the Gail model.

## Honors

**Outstanding Mentor Award****                  Dolph Hatfield, Ph.D.                               Chief, Molecular Biology of Selenium Section, CCR**

**Elected to the National Academy of Sciences April 25**
**Carl Wu, Ph.D.**
**Chief, Laboratory of Molecular Cell Biology**

**Notes:**
Nationally Recognized CCR Investigators 

National Academy of Science (8)
Sankar Adhya
John Coffin
Susan Gottesman
Ira Pastan
Michael Potter
Thomas Waldmann
Sue Wickner
Carl Wu

Institute of Medicine (6)
Michael Gottesman
Stephen Katz
Claude Klee
Douglas Lowy
Steven A. Rosenberg
Thomas Waldmann

## Honors for caBIG

**21st Century Achievement Award****—****Science**
***Computerworld *****magazine**

## Appointments

**Paul Meltzer, M.D., Ph.D.****                      Chief, Genetics Branch and Head, Clinical Molecular Profiling Core, CCR**

**Dr. Mark Udey, M.D., Ph.D.**
**Deputy Director, CCR**

**Margaret Tucker, M.D.****	****                Director, Human Genetics Program, DCEG**

## Coordinating Center for Clinical Trials

**Sheila Prindiville, M.D., M.P.H., Director**
**Program Directors:**
**Deborah Jaffe, Ph.D.**
**LeeAnn Jensen, Ph.D.**
**Ray Petryshyn, Ph.D.**

## Receiving Tenure at CCR

**Philip Dennis****, M.D., Ph.D.**
**Medical Oncology Branch & Affiliates**

**Steven Hou****, Ph.D.**
**Mouse Cancer Genetics Program**

**Steven Libutti****, M.D.**
**Surgery Branch**

**Stanley Lipkowitz****, M.D., Ph.D.**
**Laboratory of Cellular and Molecular Biology**

## Trans-NIH Programs

**TARP: Trans-NIH Angiogenesis    Research Program **
**Planning for:**
**Embryogenesis and cancer development**
**Cancer stem cells and stem cell biology**

**Notes:**
Formally presented TARP to IC Directors in February, 2006; voted one of the highest priority areas for IC Directors 2008 Budget Retreat
The first ranked budget initiative was NCI, NHGRI (Human Genome), NHLBI (Heart, Lung and Blood)  and NIMH (Mental Health) –Prospective Pharmacogenomics:   Pathway to Personalized medicine.  NCI’s section was Optimizing Chemoprevention.  Data from 2 randomized controlled trials the Adenoma Prevention with Celecoxib (APC) and Prevention of Sporadic Adenomatous Polyps (Pre-SAP) confirmed celecoxib’s efficacy in reducing adenoma recurrence in patients at moderate risk for colorectal cancer.  Samples from the APC trial are being analyzed in a retrospective pharmacogenomic assessment focused on known polymorphisms in CYP2C9 and/or UGT1A1.  Others NHLBI – Preemption of adverse events and NIMH - Selection of optimal treatment.  
Embryogenesis and Cancer Development – led by Dr. David Salomon – group is being established
Cancer Stem cells and Stem Cell Biology - Led by Dr. Ron McKay and Dr. John Niederhuber – interactions and collaborations on the NIH campus; JN invited to lecture at the Cold Spring Harbor summer course

## New Trans-NCI Programs

**Lung Cancer Program**
**Breast Cancer Stamp Premalignancy Research Program **
**Planning for programs in:**
** ****Epidemiology and Prevention**
** ****Computational Biology and Biostatistics**

**Notes:**
Lung Cancer Program – led by Dr. John Niederhuber – holding monthly meetings with NCI, NIDCD (Natl Inst. on Deafness and other Communicaton Disorders-Carter vanWaes, head and neck surgeon) and NIDCR(Natl Inst. of Dental and Craniofacial Research – Dr. Sylvio Gutkind – oral and pharyngeal cancer branch)

Planning for Epidemiology and Prevention – Strong expertise in both areas within the Institute.

Planning for Mathematics and Biostatistics – John Weinstein and Ken Buetow – expand and recruit for mathematicians and systems experts – Establish a research and service program. 

## Cancer Center Directors’ Retreat

**Subcommittees**
**Prevention****; Dr. David Alberts, Chair**
**Early Detection****; Dr. Stan Gerson, Chair**
**Treatment****; Dr. Martin Abeloff, Chair**
**Survivorship****; Dr. William Dalton, Chair**
**Coordination and Integration****; Dr. Leland Hartwell, Chair **
**Dissemination****; Dr. Ron Herberman, Chair**
**At-large members****: Drs. Judy Gasson, John Kersey and Frank McCormick**

**Cancer Center Directors’ Retreat**

**Notes:**
Cancer Center Directors Working group established in November 2006, to describe ways in which Cancer Centers can coordinate and integrate their activities to facilitate reducing the burden of cancer.

A series of teleconferences occurred over the winter, and the members presented their draft document to the Cancer Center Directors at the May, 2006 retreat 

Further refinement of the report will occur this summer. 

The report will be submitted to the Centers Subcommittee of the NCAB in August, 2006, and presented to the NCAB at their September, 2006 meeting. 

## Director’s Consumer Liaison Group 

**Listening and Learning Together:  Building a Bridge of Trust**
**A summit for the cancer advocacy community**
**June 19-20, 2006; Natcher Conference Center**
**Dedicated to the work of Ms. Nancy Caliman (former DCLG Executive Secretary)**

**Notes:**
Summit hosted for the Cancer Advocacy Community by the NCI DCLG – chaired by Doug Ulman
Lectures, Tours of the Clinical Center, Children’s Inn, National Library of Medicine – first hand look at the missions of NCI and NIH
Poster viewing and exhibits

## FY 2007 President’s Budget

**(dollars in thousands)**

| FY 2006 Appropriation | $4,793,356 |
| --- | --- |
| FY 2007 President’s Budget | $4,753,609 |
| Difference ’06 to ’07 |    - $39,747 |
| Percent Change ’06 to’07 |       - 0.8% |

## ?

**?**

**NCI’s Congressional Appropriations, FY 1998 to FY 2007**

## What is driving NCI’s budget woes?

**Federal deficit, Defense and Homeland Security priority requirements, Katrina, pandemic flu and domestic budget cuts (-2.7% for HHS)**
**Sense in Congress that “Doubling Mission” was accomplished: show us how this has gotten us closer to the goal**
**Overall support for NIH is still good. No cuts for NIH even though HHS total is down 2.7% and NCI down 0.8%**
**Decreases compounded by biomedical research inflation (BRDPI), which is around 4%**

**Notes:**
BRDPI  = Biomedical Research and Development Price Index

## NCI’s Unsolicited RPGs Far Outnumber Solicited

**Unsolicited**

**Solicited**

**NCI’s Unsolicited RPGs Far Outnumber Solicited**

- John E. Niederhuber, MD June 2006

## Slide 19

## Nearly as Many Competing Applicants in the Last 2 Years as During the NIH Doubling

***Period of NIH doubling     NCI 80% increase***

**Nearly as Many Competing **_**Applicants**_** in the **_**Last 2 Years**_** as During the NIH Doubling**

- _FY 2003_

- _FY 2005_

- 5,050

- 4,251

**799**

- _FY 1999_

- _FY 2003_

- 4,251

- 3,289

**962**

- John E. Niederhuber, MD June 2006

***Last 2 Years***

## Nearly as Many Competing Applications in the Last 2 Years as During the NIH Doubling

***Period of NIH doubling     NCI 80% increase***

**Nearly as Many Competing **_**Applications**_** in the **_**Last 2 Years**_** as During the NIH Doubling**

- _FY 2003_

- _FY 2005_

- 6,325

- 5,249

**1,076**

- _FY 1999_

- _FY 2003_

- 5,249

- 3,878

**1,371**

- John E. Niederhuber, MD June 2006

***Last 2 Years***

## RPG Competing Applications and Applicants FY 1995 to 2005

- Success Rate Based on Applications or Individual Applicants

**RPG Competing Applications and Applicants FY 1995 to 2005**

- R01 Equivalent includes R01, R29 and R37

**31.2%**

**35.4%**

**24.3%**

**23.3%**

**29.7%**

**32.6%**

**32.1%**

**27.1%**

**20.4%**

**30.1%**

**26.6%**

**20.4%**

## Applications, Awards & Success Rates: 1998 to 2007 Estimate Competing RPGs

**Applications, Awards & Success Rates: 1998 to 2007 Estimate Competing RPGs**

**Projected**

## Annualized Growth of the NIH Budget, 1971 to 2005

- 25
- 20
- 15
- 10
- 5
- 0
- -5
- -10

- 1970  1975  1980  1985  1990  1995  2000  2005

**Growth (%)**

**Fiscal Year**

- Source: Loscalzo, NEJM (2006)

## Burden of Illness FY 2006 Estimates

| Cancer Site | Deaths | Funding, in thousands | New Cases |
| --- | --- | --- | --- |
| Lung | 162,460 (1) | $264, 806 (3) | 174,470 (3) |
| Colon/Rectum | 55,170 (2) | $251,874 (4) | 148,610 (4) |
| Breast | 41,430 (3) | $557,252 (1) | 214,640 (2) |
| Pancreas | 32,300 (4) | $ 66,671 (11) | 33,730 (10) |
| Prostate | 27,350 (5)
 | $312,043 (2) | 234,460 (1)
 |

**(Blue numbers are ranks)**

## Lung Cancer, 1975-2003

_**Incidence**_
**Decline began in 1982 for men**
**Long term increase for women appears to be starting to decline**

_**Mortality**_
**Decline for men since 1991**
**Increase for women is slower since 1995**

**Lung cancer SEER incidence and U.S. death rates, 1975-2003**

**1975**

**1982**

**1989**

**1996**

**2003**

**Year of Diagnosis/Death**

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**Rate per 100,000**

**Males**

**Females**

**Males**

**Females**

**Mortality**

**Incidence**

**Delay Adjusted**

**Delay Adjusted**

## Members of Lung I2

**Margaret Spitz, Ph.D., Chair****	****	****	****	****	****    **M.D. Anderson Cancer Center
**Christine Berg, M.D.****	****	****	****	****	****           **Division of Cancer Prevention
**Neil Caporaso, M.D.**					           Division of Cancer Epidemiology 	            				    and Genetics
**Phil Dennis, M.D., Ph.D.****	****	****	****	****	****              **Center for Cancer Research
**Scott Leischow, Ph.D****	****	****	****	****	****            **Division of Cancer Control and 				        Population Sciences
**Suresh Mohla, Ph.D.****	****	****	****	****	****           **Division of Cancer Biology
**Cherie Nichols, M.B.A.****	****	****	****	****	****	**** **Office of Science Planning & 				     Assessment

**Jack Ruckdeschel, M.D.****	****   **Karmanos Cancer Institute** **
**Samir Sauma, Ph.D.**	         Office of Science Planning & Assessment
**Scott Saxman, M.D.**	      Division of Cancer Treatment and Diagnosis
**Eva Szabo, M.D.**		     Division of Cancer Prevention
**Peter Ujhazy, M.D., Ph.D.**	        Organ System Branch, ODDES
**Gary Dorfman, M.D.**	              U. of Mass Med Center; Brown U. IPA, Cancer Imaging Program

## Lung Cancer I2 Team Recommendations

**Organizational structure and program leadership**
**an operational focus for lung cancer**
**Cancer Intervention & Surveillance Modeling Network (CISNET)**
**Tobacco control**
**smoking cessation/prevention**
**biology of addiction**
**therapy of addiction**
**Early detection**
**New drug development & response to therapy**
**lung cancer biology RFA**
**imaging response to therapy**
**workshops**

**$2,900,000**

**$600,000**

**$400,000**

**$1,250,000**

**$3,200,000**

**Total:****  ****$8,350,000**

## NCI Lung Cancer Program

**April 2006:**** Dr. Niederhuber convened a meeting at AACR to discuss the NCI Lung Cancer Program**
**Goals: to organize a structure for the allocation of NCI’s resources towards lung cancer research on the basis of the Lung I2 team recommendations**
**May 2006:**** Follow-up teleconference to discuss interim progress including:**
**Discussions with FDA on joint clinical trial**
**Meeting with Division of Cancer Biology**
**Trans-NCI lung investigator meeting **

## Lung Cancer Initiatives

_**Governance**_
**Recruit Program Director**
**CISNET supplements**

_**Governance**_
**Recruit senior clinician to oversee lung cancer program, coalesce and expand expertise at NCI**
**CISNET supplements**

**Lung Cancer I2 Team**

**Lung Cancer Program**

## Lung Cancer Initiatives

_**Governance**_
**Recruit Program Director**
**CISNET supplements**
_**Early detection**_
**NLST biorepository, processing, archive and database**

_**Governance**_
**Recruit senior clinician to oversee lung cancer program, coalesce and expand expertise at NCI**
**CISNET supplements**
_**Early detection**_
**Support NLST biorepository**

**Lung Cancer I2 Team**

**Lung Cancer Program**

## Drug Development
Lung cancer biology RFA
Workshop for drug delivery strategies; anti-angiogenesis

**Lung cancer biology RFA**
**Workshop for drug delivery strategies; anti-angiogenesis**

_**Drug Development**_
**Lung cancer biology RFA**
**Biomarkers trial in NSCLC with FDA and CMS**
**Early phase epigenetic trial**

**Lung Cancer Initiatives**

**Lung Cancer I2 Team**

**Lung Cancer Program**

## Drug Development
Lung cancer biology RFA
Workshop for drug delivery strategies; anti-angiogenesis

**Lung cancer biology RFA**
**Workshop for drug delivery strategies; anti-angiogenesis**

_**Drug Development**_
**Lung cancer biology RFA **
**Biomarkers trial in NSCLC with FDA and CMS**
**Early phase epigenetic trial**

**Lung Cancer Initiatives**

**Lung Cancer I2 Team**

**Lung Cancer Program**

_**Imaging**_
**Response to therapy**

_**Imaging**_
**Novel imaging probes to monitor tumor uptake in early phase epigenetic trial**

**Notes:**
Funding for imaging component of Lung Cancer Program is $1 million.

## Tobacco Control
Genetics of nicotine dependency
Tobacco informatics grid
Workshops

**Genetics of nicotine dependency**
**Tobacco informatics grid**
**Workshops**

_**Tobacco Control**_
**Leverage outside resources**
**187 funded projects= ~$137M**
**tobacco control**
**mechanisms of nicotine addiction**

**Lung Cancer Initiatives**

**Lung Cancer I2 Team**

**Lung Cancer Program**

**Notes:**
Today is the final day of the NIH State-of-the-Science Conference on Tobacco Use: Prevention, Cessation and Control. Dr. Clanton gave opening remarks on Monday.

NCI Tobacco Control portfolio analysis - 187 projects relevant to Tobacco Control and Mechanisms of Nicotine Addiction.  Total FY2005 funding ~$137M.

## Genetic Susceptibility to Lung Cancer

**Strong evidence of linkage under heterogeneity in 6q region**
**LOH, CGH studies support this as a lung cancer susceptibility region**
**Additional suggestive evidence of linkage under heterogeneity in several other regions**
**Suggests that there are major loci for lung cancer susceptibility**
**Sequencing ongoing in over 100 candidate loci in 6q23**
**Fine-mapping planned in the strongest linkage regions**
**Family data collection is continuing**

- Wiest Laboratory

## Lung Cancer Drug Development: The Akt/mTOR Pathway

**Lung Cancer Drug Development: ****The Akt/mTOR Pathway**

**Notes:**
This pathway is an important target in lung cancer because it is activated by many molecular alterations that are characteristic of lung cancer, including activation of receptor tyrosine kinases such as EGFR, activation of receptors for angiogenic factors such as VEGF, activation of receptors for tobacco components, and activation of Ras.  The signal to Akt is propagated to many downstream substrates including mTOR.  Ultimately, this pathway controls many critical cellular processes in cancer such as cell cycle progression, metabolism, protein translation, cellular survival, and gene transcription. 

## Prevention

***Tobacco components activate the pathway in normal human airway cells***

**Notes:**
Critical studies from Dr. Dennis’ group have identified the Akt/mTOR pathway as a target for prevention of lung cancer.  His group showed that two tobacco components, nicotine and the carcinogen, NNK, rapidly activate the pathway in normal human lung epithelial cells.  This is shown in here.  Activation occurred within minutes at concentrations that are achievable in smokers, and could be inhibited with a pathway inhibitor (LY) or nicotinic antagonists (DHBE, BTX).  

## Prevention

**Progression**

**Prevention**

***Pathway activation correlates with progression of tobacco carcinogen-induced lung lesions***

**Notes:**
In support of the gatekeeper hypothesis, his group showed that activation of Akt and mTOR increased with phenotypic progression of tobacco-induced lung lesions in a mouse model of lung cancer

## Prevention

**Number**

**Size**

**Prevention**

***An FDA-approved mTOR inhibitor, rapamycin, decreases number and size of tobacco carcinogen-induced lung lesions***

**Notes:**
Most recently, his group showed that an mTOR inhibitor, rapamycin FDA-approved for other indications, inhibited the number of tobacco carcinogen-induced lung lesions by 90%, as well as tumor size in comparison to vehicle control.

## Prevention

**Impact:**
**Conceptual shift in tobacco-related carcinogenesis**
**Pathway activation as biomarker in prevention trials**
**Provides strong rationale to test mTOR inhibitors for lung cancer prevention**

**Notes:**
Together, these studies have changed the concept of how tobacco causes lung cancer, and have raised awareness of pathway activation as a biomarker for prevention studies.  Importantly, they provide a strong rationale to use MTOR inhibitors in human lung cancer prevention trials.

## Treatment

**Preclinical**

**Phosphatidylinositol ether lipid analogues (PIAs)**

**Treatment**

**Clinical**

- Early phase clinical protocols
- 	Phase 0 trials- PIAs
- 	Phase I, II trials - rapamycin + chemotherapy, “off the shelf” pathway 		inhibitors

**Notes:**
Despite the strong rationale to target Akt, no Akt inhibitors are clinically approved.  Dr. Dennis has led a large collaborative effort in academia, industry and the Developmental Therapeutics Program at NCI, to develop lipid-based inhibitors of Akt called phosphatidylinositol ether lipid analogues (or PIAs).  PIAs were synthesized using molecular modeling of Akt (upper left panel), and Dr. Dennis and his colleagues at Georgetown University are co-inventors of PIAs.  Unlike most pharmaceutical efforts to develop Akt inhibitors that have focused on the ATP binding domain, the PIAs that Dr. Dennis is developing target the pleckstrin homology (PH) domain.  His group has identified 5 active PIAs that inhibit Akt within minutes and selectively kill cancer cells with high levels of Akt activation.  More recently, his group has identified other biological effects of PIAs (shown on right) that include induction of key tumor suppressor genes such as KLF2, KLF6, and RhoB that could be used as biomarkers for adminstration of PIAs.  PIAs have been identified by DCTD as candidates for first in human trials, so called “Phase 0” protocols.  
As clinical service director of the oncology clinic at NCI/Navy, Dr. Dennis is complementing these preclinical efforts to develop Akt inhibitors with implementation of clinical trials that are testing inhibitors of the Akt/mTOR pathway in lung cancer patients.  In addition to the proposed Phase 0 trial with PIAs, these trials include a protocol combining rapamycin with pemetrexed, a standard second line agent in advanced NSCLC treatment, as well as a protocol to test an HIV protease inhibitor as an “off the shelf” inhibitor of Akt in lung cancer patients.  Together, these studies could increase therapeutic options for lung cancer patients and could shed insight into the clinical benefit achieved by inhibiting the Akt/mTOR pathway. 

## Determine steps in tobacco-mediated activation of Akt
Develop new models of lung cancer that incorporate genetic modifications of the Akt/mTOR pathway
Identify new PH domain-targeted Akt inhibitors using bioinformatics and in silico screening
Refine clinical trials in lung cancer to individualize therapies based on expression of specific molecular targets 
Develop consortium with Johns Hopkins FAMRI Center of Excellence to expedite drug development for lung cancer patients.

**Develop new models of lung cancer that incorporate genetic modifications of the Akt/mTOR pathway**
**Identify new PH domain-targeted Akt inhibitors using bioinformatics and *****in silico***** screening**
**Refine clinical trials in lung cancer to individualize therapies based on expression of specific molecular targets **
**Develop consortium with Johns Hopkins FAMRI Center of Excellence to expedite drug development for lung cancer patients.**

**Current Efforts**

**Notes:**
Current efforts of the group led by Dr. Dennis include:
1.  Determining steps in tobacco-mediated activation of Akt
2.  Developing new models of lung cancer that incorporate genetic modifications of the Akt/mTOR pathway
3.  Identifying new PH domain-specific Akt inhibitors through advanced bioinformatics and in silico screening.  
4.  Refining clinical trials in lung cancer to individualize therapies based on expression of specific molecular targets such as active components in the Akt/mTOR pathway.
5.  Developing a consortium with Johns Hopkins FAMRI Center of Excellence to expedite drug development for lung cancer patients.  

## Burden of Cervical Cancer

**Burden of Cervical Cancer**

**Incidence**
**9,710 cases estimated in U.S. in 2006**
**470,000 cases per year worldwide**
**Deaths**
**3,700 estimated deaths in U.S. in 2006**
**233,000 deaths per year worldwide**

**Notes:**
Top Figure:  Pap Smear slide with CIN 1.

Bottom Figure: invasive squamous cell carcinoma of cervix 

## Current Prophylactic Vaccines are Based on 

**Purified Papillomavirus-Like Particles (VLPs)**

**Empty shells composed of only the L1 major virion protein***
**Induce high titers of virion-neutralizing serum antibodies after IM injection***
**Non-infectious and non-oncogenic**
**Vaccination with VLPs of animal PVs induces type-specific protection from experimental infection with high dose virus**
**Protection passively transferred in serum**
**No regression of established lesions **
**No sexual transmission model**

****Kirnbauer et al. PNAS 89:12180-4, 1992***

## HPV VLP Vaccines in Phase III Trials

**                                    ****HPV18**
**                                    ****ASO4 Adjuvant ****(MPL + Alum)**
**                                    ****Made in insect cells**
**Merck:****	****	****    HPV16**
**	****	****	****    ****HPV18**
**	****	****	****    ****HPV6**
**	****	****	****    ****HPV11**
**	****	****	****    ****Alum Adjuvant**
**	****	****               ****Made in yeast****	****	**

**70% of Cervical Ca**

**70% of Cervical Ca**

**90% of Genital Warts**

**HPV VLP Vaccines in Phase III Trials**

**IM Injections at 0, 1 or 2, and 6 months**

## Merck Phase 3 Tetravalent Vaccine:Interim Analysis (Unpublished)

|  | Vaccine
(N = 2717) |  | Placebo
(N = 2725) |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | n | Cases | n | Cases | Efficacy    (%) | CI |  P Value  |
| CIN or worse | 2240  | 0 | 2258 | 37 | 100 | (87–100)  | <0.001          |
| Genital warts, vulvar/vaginal neoplasia | 2261 | 0 | 2279 | 40 | 100 | (88–100) | <0.001 |

**ATP**** = received 3 doses of vaccine; HPV sero(-) at day 1 and HPV DNA(-) from day 1 to month 7;**
**        ****cases counted starting after month 7.**
**Average Duration of Follow-up: ****1.5 Years After the Last Vaccination**

**ATP analysis.  HPV6,11,16, 18 Associated Disease Only**

**Notes:**
Key point
Results from the FUTURE I study show that GARDASIL® was 100% efficacious against CIN or worse lesions, as well as genital warts and VIN/VaIN related to HPV in a population of female subjects naïve to HPV 6/11/16/18 until completion of vaccination.

Background 
In this study, prophylactic quadrivalent HPV vaccination with GARDASIL® prevented 100% of HPV-related CIN or worse lesions, as well as genital warts, and VIN/VaIN in female subjects who were not infected with HPV at enrollment and who remained free of infection through the completion of the vaccine regimen (month 7).1

The subjects had a follow-up for an average of 2 years after the first vaccination.1 

This intervention is expected to reduce the risk of cervical cancer, vulvar/vaginal cancers, and other clinical diseases caused by HPV.1

GARDASIL is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

Reference 
1. Data on file, MSD.

## Will the HPV Vaccine Reach the Women Who Need it Most?

**0**

**2**

**00**

**4**

**00**

**6**

**00**

**2**

**00**

**4**

**00**

**6**

**00**

**Breast**

**Cervix**

**Ovary**

**Endometrium**

**Annual number of cases (thousands)**

**More**

** ****developed **

**countries**

**Less**

*** *****developed***** ***

**countries**

**Colon/rectum**

**Lung**

**Stomach**

- Adapted from Parkin et al, Eur J Cancer 37:S4, 2001

**“****Pap” smear**

**Notes:**
IARC slides from Nubia Munoz, Year 2000 IARC

## Vaccine Policy, United States

**Greatest benefit if given to 10-13 year old girls or older girls/women who have not become sexually active**
**Make available to poorer women**
**Vaccinated women must continue to follow standard guidelines for cervical cancer screening**
**Vaccination before becoming sexually active **_**and**_** screening after becoming sexually active could ****reduce cervical cancer by more than 90%**

## Vaccine Policy, Developing World

**80% of cervical cancer cases occur in the developing world**
**Currently lacks high-quality screening programs**
**Screening is useful for current generation**
**Vaccination, because it should be given to adolescents, is useful for the next generation**
**Reduction in cost of vaccine or organized distribution program will be needed**

**Notes:**
HPV vaccine development started at NCI – Doug Lowy, John Schiller  (CCR) and out of DCEG Allan Hildesheim and Mark Schiffman are conducting a clinical trial in Costa Rica 

## Summary of HPV VLP VaccineEfficacy Data in Women

**Vaccine well tolerated; no vaccine-related SAEs**
**>99% seroconversion**
**95-100% protection from persistent infection by the types in the vaccine**
**100% protection from cervical pre-cancer by the types in the vaccine (up to 4 yrs post vaccination)**
**100% protection against external genital warts**
**Limited or no protection against types not in the vaccine**
**No evidence for inducing regression of preexisting lesions**

## In Memoriam: Dr. Anita Roberts

**“****I’m quickly approaching the end of my journey... I’ve been rapidly losing ground to this disease and I’ve now come home to end my life’s journey in peace.”**

***Excerpted from the final entry of Anita Roberts’ online journal, Wednesday, May 10, 2006***

**May 26, 2006**

## A Lifetime of Accomplishments

**Ph.D. from University of Wisconsin **
**Postdoctoral Research at Harvard**
**Chief, Laboratory of Cell Regulation                                       and Carcinogenesis in CCR**
**Second-most-cited female scientist                                        in the world**
**In collaboration with Michael Sporn                              conducted seminal research into the role of TGF****ß**
**FASEB Award for Excellence in Science**
**Susan G. Komen Foundation’s Brinker Award for Scientific Distinction**

## Slide 53

## HPV Virus-Like Particle Vaccine

**Vaccination**

**HPV Virus-Like Particle Vaccine**

**VLPs**

**Endocervix**

**Transformation**
**Zone**

**Cervical **
**Mucus**

**Ectocervix**

**Neutralizing**
**Antibodies**

**Intramuscular**

## HPV and Cervical Cancer

- 92.9% of 932 cases of invasive cervical cancer worldwide tested positive for HPV DNA in 1995 IARC study

| HPV Type | Infections | Percent |
| --- | --- | --- |
|     HPV 16 | 465 | 49.9 |
|     HPV 18 | 128 | 13.7 |
|     HPV 45 | 78 | 8.4 |
|     HPV 31 | 49 | 5.3 |
|     HPV 33 | 26 | 2.8 |
|     Other HPV | 156 | 16.7 |
|     HPV neg | 66 | 7.1 |

- Of the 66 HPV neg cases, the 34 histologically adequate samples were later reanalyzed with more sensitive techniques. Only 2 were in fact HPV negative.
- Combined results yield 99.7% of ICC cases were HPV positive

- Walboomers et al Journal of Pathology 189: 12 – 19 1999

**Notes:**
IARC – International Agency for Cancer Research

% breakdown by type with new results are:
HPV 16 – 53%
HPV 18 – 15%
HPV 45 -  9%
HPV 31   6%
HPV 33 3%

In addition to the prevalence study that established HPV as the causative agent for cervical cancer, the following studies were also done:
The second set of studies included case-control studies carried out in 13 countries. They included about 2000 cases and 2000 controls. Positivity, for any HPV DNA yielded a pooled odds ratio (OR) of 70. The association was equally strong for both squamous cell (OR=74) and adenocarcinoma (OR=50) and for HPV 16 and 18 as well as for the less common HPV types. Our results indicate that in addition to HPV 16 and 18, HPV 31, 33, 35, 45, 51, 52, 58 and 59 now can be considered as carcinogenic. 
The third group of studies is aimed to determine the HPV DNA prevalence in random, age-stratified (by 5 years, 15-19 to 65+) subsamples (1100 women) of the general population. Two age-peaks (<25 and >59 years), have been found in some countries (Costa-Rica, Mexico, Colombia) but not in all (Argentina). Whether the second peak is due to viral reactivation, variations in screening or represents a birth-cohort effect remains to be determined. The distribution of the most prevalent HPV types in the general population (HPV 16, 18, 45, 31, 58, 33, and 35) resembles that for cervical cancer cases. 
J Clin Virol 2000 Oct 1;19(1-2):1-5: 
Human papillomavirus and cancer: the epidemiological evidence. 
Munoz N, International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372, Cedex 08, Lyon, France. 

## Timeline: HPV Vaccine Development

**HPV: human papillomavirus; VLP: virus-like particle**

**First VLPs produced**

**Initial report of efficacy**

**HPV16 and HPV18 discovered**
**(1982-1992)                  Activities of HPB oncogenes determined**

**HPV proposed as a necessary cause of cervical cancer**
**VLP clinical trials begin**

**Vaccine licensure**

**(1995-2001) Prospective HPV neoplasia studies**

**(1990-1998)           Case control/cervical cancer studies**

**Notes:**
Merck filed with FDA in Dec. ‘05.

  FDA Advisory Panel (VRBPAC) recommended approval
   for prophylactic vaccination of females 9-26 yr., May ‘06.

 A decision is expected in June ‘06.

 GSK filed in Europe Mar. ‘06, decision expected within one   year. FDA filing expected before end of the year.

## Prevention

**Mutations and other changes: RAS, NYC, p53, p16, RB, FHIT & other critical genes**

**Prevention**

**Akt activation**

**A biochemical gatekeeper for tobacco-related cancers? **

**Nicotine Addiction**

**PAH, NNK and other carcinogens**

**DNA adducts**

**Lung cancer**

**Cigarette smoking**

**Excretion**

- Metabolic detoxification

**Metabolic activation**

**Persistence/ Miscoding**

**Apoptosis**

- Repair

**Normal DNA**

**Notes:**
Because activation of Akt caused a partially transformed phenotype through inhibition of apoptosis and decreased reliance on extracellular growth factors, Dr. Dennis has hypothesized that Akt activation serves as a biochemical gatekeeper for tobacco-related carcinogenesis.  

## Early Detection: Evidence for Genetic Risk in Lung Cancer

**Several lines of evidence show that genes play a role in lung cancer, and that individuals may differ in their susceptibility to the pertinent environmental insults.**
**Are there genes that have LARGE effects on risk of lung cancer similar to BRCA1, BRCA2, etc.?**

**Early Detection: Evidence for Genetic Risk in Lung Cancer**

## New Investigators

**All applicants at Assistant Professor rank will not have their applications triaged**
**Full detailed review with written critiques**
**Value of critique for A1, A2 resubmissions**
**New grant application section designed to assure institution review and support**
**Faculty oversight committee for monitoring progress of the Assistant Professor**
**Written section will summarize work of the committee**
**NCI’s workshop for first-time grantees**
**Metrics should be established to evaluate the value of the change**

**Notes:**
Maximize the chances for successful grant applications by our new tenured track assistant professors, as well as to maximize their chances for receiving tenure.  In addition to achieving their first successful R01 as a beginning faculty member, new faculty have, at most Universities, a six-year time-frame in which to demonstrate scientific accomplishments and recognition in the field of research they have chosen.  An important factor to the tenure/promotion decision in year seven is the successful competing renewal of their first NIH grant award.  The following suggestions for enhancing success rates are derived from my years as a member of a research faculty as well as a clinical faculty member.  My ideas have been shaped by my personal experience but also by recent discussions with young faculty at several academic institutions.  
Division of Cancer Biology annually sponsors a New Grantee’s Workshop attended by ~100 new investigators. 

Met with Dr. Norka Ruiz Bravo (Deputy Director for Extramural Research) to discuss changes.  Submitted formal request to Extramural Program Management Committee (EPMC) May, 2006.

## This is what I hear from the extramural community!

**“****Too much emphasis on translational ****a****science away from basic science!”**
**“****NCI is funding too many big projects                                                                                                              and initiatives.”**
**“****RFAs, PAs  are taking money away ****a****from unsolicited grant applications.”**
**“****It’s the Roadmap!”**

**Notes:**
Speak

## CGEMS: Cancer Genetic Markers of Susceptibility

**Capitalizing on advances in human genetic research**
**Three-year, $14M initiative**
**Identify genetic alteration of susceptibility to prostate and breast cancer**
**Using DNA from five large studies for each cancer**
**“****Scan” genome for variations between patients and control subjects**

**Notes:**
Coordinated out of DCEG – Led by Drs. David Hunter and Steve Chanock

## Prevention

**Prevention**

***Tobacco components activate the pathway in normal human airway cells***

**Notes:**
Critical studies from Dr. Dennis’ group have identified the Akt/mTOR pathway as a target for prevention of lung cancer.  His group showed that two tobacco components, nicotine and the carcinogen, NNK, rapidly activate the pathway in normal human lung epithelial cells.  This is shown in the upper left panels.  Activation occurred within minutes at concentrations that are achievable in smokers, and could be inhibited with a pathway inhibitor (LY) or nicotinic antagonists (DHBE, BTX).  

## Prevention

**A biochemical gatekeeper for tobacco-related cancers? **

**Notes:**
Because activation of Akt caused a partially transformed phenotype through inhibition of apoptosis and decreased reliance on extracellular growth factors, Dr. Dennis has hypothesized that Akt activation serves as a biochemical gatekeeper for tobacco-related carcinogenesis.  

## Prevention

- _Impact_
- *Conceptual shift in tobacco-related carcinogenesis
- *Pathway activation as biomarker in prevention trials
- *Provides strong rationale to test mTOR inhibitors for lung cancer prevention

- 1.  Tobacco components activate the pathway in normal human airway cells

**Notes:**
Critical studies from Dr. Dennis’ group have identified the Akt/mTOR pathway as a target for prevention of lung cancer.  His group showed that two tobacco components, nicotine and the carcinogen, NNK, rapidly activate the pathway in normal human lung epithelial cells.  This is shown in the upper left panels.  Activation occurred within minutes at concentrations that are achievable in smokers, and could be inhibited with a pathway inhibitor (LY) or nicotinic antagonists (DHBE, BTX).  Because activation of Akt caused a partially transformed phenotype through inhibition of apoptosis and decreased reliance on extracellular growth factors, Dr. Dennis has hypothesized that Akt activation serves as a biochemical gatekeeper for tobacco-related carcinogenesis (advance slide).  In support of this hypothesis, his group showed that activation of Akt and mTOR increased with phenotypic progression of tobacco-induced lung lesions in a mouse model of lung cancer (upper right panels) (advance slide).  Most recently, his group showed that an mTOR inhibitor, FDA-approved for other indications, inhibited the number of tobacco carcinogen-induced lung lesions by 90%, as well as tumor size (advance slide).  Together (advance slide), these studies have changed the concept of how tobacco causes lung cancer, and have raised awareness of pathway activation as a biomarker for prevention studies.  Importantly, they provide a strong rationale to use mTOR inhibitors in human lung cancer prevention trials.

## NCI’s Allocation of 2007 Request $4.8 Billion

**Cancer Control**
**11%**

**Other 5%**

**Training 4%**

**Coop Groups 3%**

**Intramural 15%**

**SPOREs 3%**

**Cancer Centers 6%**

**Research Project Grants**
**46%**

**NCI’s Allocation of 2007 Request $4.8 Billion**

**R&D Contracts**
**7%**

**- Support 6%**

**- Research 9%**

- John E. Niederhuber, MD June 2006

## Appropriations Hearings

**Accompanied Dr. Zerhouni                 to House Hearings April 6**
**Senate Hearings May 19,         provided supplemental             testimony:**
**Funding needed to carry The Cancer Genome Atlas forward**
**Funding needed to win the war on cancer overall **

**Notes:**
Supplemental testimony on The Cancer Genome Atlas explained the nature of the project – a collaboration between NCI and NHGRI—the kinds of genetic alterations that contribute to cancer and how, if these alterations were known, will provide the necessary scientific data to target the changes. 

Supplemental testimony on a winning strategy against cancer –
4 strategic objectives to preempt cancer:
Understand the causes and mechanisms of cancer
Accelerate progress in cancer prevention
Improve early detection and diagnosis
Develop effective and efficient treatments
4 strategic objectives to ensure best outcomes
Understand the factors that influence cancer outcomes
Improve the quality of cancer care
Improve the quality of life for patients, survivors and their families
Overcome cancer health disparities
These will require numerous funding vehicles and support mechanisms, flexible legislative authorities

## Overall NCI Budget

|  | FY 2006 Appropriation | 
FY 2007 PB | 
Change
 |
| --- | --- | --- | --- |
| Total Res. Grants | $2,947,764 | $2,894,978 | -1.8% |
| NRSA |  66,619 | 66,279 | -0.5% |
| R&D Contracts | 326,560 | 330,441 | 1.2% |
| Intramural Research | 699,763 | 696,263 | -0.5% |
| Rsch. Mgt. & Support | 182,246 | 183,246 | 0.5% |
| Cancer Prev. & Control | 519,650 | 517,100 | -0.5% |
| Repair & Improvement | 7,920
 | 7,920 | 0.0% |
|           Total, NCI | 4,750,522 | 4,696,227 | -1.1% |
| NIH Roadmap | 42,834 | 57,382 | 34.0% |
|           Total NCI w/ Roadmap | 4,793,356
 | 4,753,609 | -0.8% |

**(dollars in thousands)**

**Overall NCI Budget**

**Notes:**
The FY2007 NCI request includes $7.8M to support the Genes, Environment and Health Initiative (GEHI).

## STAR Trial: Study of Tamoxifen and Raloxifene

**Comparison of reduced risk of breast cancer in postmenopausal women at increase risk**
**STAR enrolled 19,747 women**
**Results show raloxifene as effective as tamoxifen in reducing risk; ~ 50%**
**Raloxifene had fewer serious side effects, including fewer uterine cancers, blood clots and cataracts**

**Notes:**
Study began in 1999 – NSABP and NCI
Increased risk was defined by:
Age
Number of 1st degree relative with breast cancer
Whether a women has had any children and her age at her first delivery
Number of breast biopsies, especially if the tissue showed atypical hyperplasia
Age of first menstrual perios
Age when she reached menopause
Tamoxifen - in use for more than 30 years to interfer with the activity of estrogen – approved by FDA in 1998 to reduce the incidence of breast cancer in women at increased risk
Raloxifene was approved in 1997 by the FDA for prevention of osteoporosis in postmenopausal women. In 1999 it was approved as an osteoporosis treatment.  The Multiple Outcomes of Raloxifene Evaluation (MORE) trial showed a reduction in the incidence of breast cancer.  

STAR showed equal efficacy
Side effects – uterine cancer  - more than half the women had hysterectomy – women in the raloxifene group developed 36% fewer uterine cancers (36/4,732 in tamoxifen group; 23/4712 in raloxifen group)
Blood clots – raloxifene group had 29% fewer deep-vein thromboses and pulmonary embolisms (87/9,726 in tamoxifen group; 35/9,745 in raloxifene group)
Cardiovascular problems – statistically equalivant – 53/9,726 in tamoxifen group; 51/9,745 in raloxifene group)
Bone fractures – similar numbers 104/9,726 in tamoxifen group; 96/9,745 in raloxifene group)
Cataracts – Tamoxifen group at 14% increased risk of developing cataracts (394/9,726 in the tamoxifen group; 313/9,745 of the raloxifene group)

Why important:  This year more than 212,000 women will be diagnosed with breast cancer, most postmenopausal and more than 40,000 will die.  This offers an alternative to tamofixen – does not replace need for mammography

## New Investigators

**All applicants at Assistant Professor rank will not have their applications triaged**
**Full detailed review with written critiques**
**Value of critique for A1, A2 resubmissions**
**New grant application section designed to assure institution review and support**
**Faculty oversight committee for monitoring progress of the Assistant Professor**
**Written section will summarize work of the committee**
**Metrics should be established to evaluate the value of the change**

**Notes:**
maximize the chances for successful grant applications by our new tenured track assistant professors, as well as to maximize their chances for receiving tenure.  In addition to achieving their first successful R01 as a beginning faculty member, new faculty have, at most Universities, a six-year time-frame in which to demonstrate scientific accomplishments and recognition in the field of research they have chosen.  An important factor to the tenure/promotion decision in year seven is the successful competing renewal of their first NIH grant award.  The following suggestions for enhancing success rates are derived from my years as a member of a research faculty as well as a clinical faculty member.  My ideas have been shaped by my personal experience but also by recent discussions with young faculty at several academic institutions.  

Met with Dr. Norka Ruiz Bravo (Deputy Director for Extramural Research) to discuss changes.  Submitted formal request to Extramural Program Management Committee (EPMC) May, 2006.

## Lung Cancer, 1975-2003

_**Incidence**_
**Decline began in 1982 for men**
**Long term increase for women appears to be starting to decline**

_**Mortality**_
**Decline for men since 1991**
**Increase for women is slower since 1995**

**Lung cancer SEER incidence and U.S. death rates, 1975-2003**

**1975**

**1982**

**1989**

**1996**

**2003**

**Year of Diagnosis/Death**

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**Rate per 100,000**

**Males**

**Females**

**Males**

**Females**

**Mortality**

**Incidence**