National Cancer Institute (NCI)

Overview of NCI Rare Diseases Research Activities

Cancer is not rare; it is, in fact, the second leading cause of death in the United States. In 2000, there will be about 1,220,100 new cases of cancer (other than nonmelanoma skin cancer), with about 552,200 deaths. These projected numbers represent a decrease from those projected for 1999, reflecting the sustained decline in overall cancer incidence and cancer death rates as reported last year. Cancer, however, is not one but many distinct diseases. Certain cancers, including breast, prostate, lung, and colon, can no longer be classified as rare diseases, because prevalence data indicate that these cancers have exceeded the 200,000 cases per year maximum for inclusion as a rare disease. Although incidence and mortality rates for most cancers have dropped, rates of malignant melanoma (now one of the most common cancers in young adults), non-Hodgkin's lymphoma, esophageal cancer, liver cancer, and kidney and renal pelvis cancers have risen.

NCI's mission is to develop the means to decrease the incidence, morbidity, and mortality of cancer. It does this through the conduct and support of research in cancer biology, cause, prevention, control, detection, diagnosis, treatment, rehabilitation, and continuing care. NCI's section of this report discusses selected major research advances, research initiatives within NCI intramural and extramural programs, and other program activities in these areas.

Recent Scientific Advances in Rare Diseases Research: Cancer Biology and Etiology

Basic research studies exploring the mysteries of how cancer develops form the foundation of cancer research. Through these studies, scientists are identifying, at the molecular level, the fundamental processes that underlie a cell's transformation from normal to malignant. The implications of this research are profound; identifying the processes and pathways that lead to cancer provides attractive targets for new prevention and treatment approaches. Likewise, elucidation of the external and internal factors that cause or contribute to cancer provides avenues for developing behavioral interventions and drugs to prevent cancer.

Origin of Melanoma

Melanoma is the most serious cancer of the skin, with U.S. incidence rates more than doubling in the past 20 years. Recent studies have identified, isolated, and characterized various specific melanogenic enzymes and structural melanosomal matrix proteins that regulate the quality and quantity of melanin produced within melanocytes. These proteins are encoded by genes that are specifically expressed by mammalian melanocytes, and mutations in several genes have now been shown to be involved in various human clinical pigmentary diseases. Because these melanocyte differentiation proteins are known to provide highly specific targets for humoral and cellular immune responses against malignant melanoma, NCI investigators have continued to examine approaches to optimize those responses and have initiated a new project to identify novel melanosomal targets. Research in this area is aimed at further characterizing those gene products and the nature of the regulatory mechanisms involved. The sum of these studies should improve understanding of processes important to the malignant transformation of melanocytes and to targeting their specific antigens for immunodetection and/or immunotherapy.

Genetic Changes in Von Hippel-Lindau Disease

Von Hippel-Lindau (VHL) disease is a rare familial disease in which affected patients usually die of kidney cancer before age 50. Clinical investigators in the NCI intramural program used this experiment of nature to identify the genetic changes in the much more common form of sporadic disease. They brought for evaluation to the clinical center nearly 800 patients who were either affected by or at risk for VHL or other inherited forms of renal carcinoma and were able to do linkage analysis to localize the VHL gene to a small region on the tip of chromosome 3. These families enabled the researchers to find the VHL gene and identify the germ line VHL gene mutation in more than 200 kindreds. Interestingly, the same suppressor gene is mutated in sporadic kidney cancer. The function of this gene and its product are under active evaluation.

Possible Tumor Suppressor Gene

The hCHK2 gene is the human homolog of a gene first identified in yeast that is involved in the G2 checkpoint of the cell cycle. Heterozygous germ line mutations in the hCHK2 gene were detected among individuals with Li-Fraumeni syndrome (LFS), a rare and highly penetrant familial syndrome characterized by multiple cancers that is usually associated with inherited mutations in the TP53 gene. These findings suggest that hCHK2 is a tumor suppressor gene that confers a predisposition to sarcoma, breast cancer, and brain tumors, and provide a link between the central role of p53 inactivation in human cancer and the well-defined G2 mitosis kinases in yeast.

Nasal and Nasopharyngeal Cancers and Chlorophenol Exposure

Work in wood-related occupations (e.g., wood treatment facilities, leather tanning facilities, sawmills) and occupational exposures to cutting oils and wood preservative chemicals have been reported to be associated with nasal and nasopharyngeal cancers. A population-based case-control study was undertaken to ascertain whether there was a relationship between chlorophenol exposure and the risk of these two cancers. Occupational information was obtained from people with nasal and nasopharyngeal carcinomas and control subjects. Both of these cancer types were significantly associated with estimated duration of chlorophenol exposure. The data support an elevated risk for chlorophenol and nasopharyngeal cancer, with a strong association after exposure for 10 or more years. Occupational exposures to formaldehyde and wood dust, which are likely to occur in wood-related industries, did not change the results, suggesting the need for future studies to assess the role of these and other agents.

Cancer Risk Among Relatives of Nonsmoking Lung Cancer Cases

Studies of lung and other cancers in nonsmokers have the potential for elucidating important causes of cancer other than tobacco exposure. This study evaluated whether the first-degree relatives of nonsmoking lung cancer cases were at increased risk for cancers at sites other than lung. Data were collected from the first-degree relatives of lung cancer cases who identified themselves as lifetime nonsmokers and nonsmoking control subjects. Moderate familial aggregation was found for cancers of the lung, digestive system, breast, and tobacco-related sites. This suggests that common susceptibility genes may act to increase risk for various cancers in families.

Malignant Glioma and Exposure to Electromagnetic Fields

Malignant glioma is a debilitating brain tumor that is rapidly fatal, yet little is known about its causes, including whether residential power frequency electromagnetic field (EMF) exposure is associated with glioma. Adults newly diagnosed with histologically confirmed glioma and matched control subjects were studied. Interviews were conducted with cases and control subjects, and information was gathered about their residences. Living in a residence with higher wire codes and spot measurements during the 7 years before diagnosis or interview was not positively associated with glioma. Adjustments for age, gender, race, and whether the person owned his/her home did not change these findings. The data do not provide support for an association between residential EMF exposure and glioma.

Genetic Basis of Chordoma

Chordoma is a rare, low-grade, malignant bone tumor (approximately 200 cases/year in the United States) that is believed to be derived from remnants of the embryonic notochord. Typically, chordoma is a sporadic tumor; only five multiplex families, each with two or three affected relatives, have been reported since 1958. One of these families was referred to NCI in 1996, a second family was identified through a study initiated with four Surveillance, Epidemiology and End Results (SEER) registries in 1999, and a third family was identified by a clinical geneticist in the United Kingdom. In the first family, four living individuals in two generations had been diagnosed with chordoma over 9 years. The 4 family members, along with 14 first- and second-degree relatives, were evaluated with MRI scans of the skull base and spine, and blood was obtained for gene mapping studies. The scans showed tumors of the clivus or nasopharynx in six additional relatives, including a parent of each of the four index cases. The histopathology of three of these tumors confirmed chordoma. The presence in the family of both affected males and females and two father-son pairs is consistent with transmission of an autosomal dominant mutation. A collaboration with a researcher at Duke University has been initiated to conduct a genomewide screen of lymphocyte DNA from all three families, and various strategies are being used to identify more chordoma families, including a new chordoma study Web site.

Genetic Basis of Human Kidney Cancer

Carcinoma of the kidney affects some 27,000 individuals in the United States each year. NCI investigators have continued their studies of families with an inherited predisposition to develop papillary renal carcinoma. They have demonstrated that mutations in the MET gene predispose to a specific histological type of papillary renal carcinoma. Studies also have continued on a rare inherited tumor of the kidney called familial renal oncocytoma. Families affected with renal oncocytoma were also affected with tumors of the hair follicle, called fibrofolliculomas. Fibrofolliculomas are the cardinal feature of a previously described inherited disorder: the Birt Hogg Dube (BHD) syndrome. Of particular interest, patients with fibrofolliculomas appear to be at increased risk for the development of kidney tumors. Blood samples and skin biopsies from family members have been collected for study in an effort to identify the BHD gene.

Recent Scientific Advances in Rare Diseases Research: Detection, Diagnosis, and Prognosis

Promotion of research to improve cancer genetic screening and early cancer detection and to develop more accurate diagnostic techniques is of major importance to NCI. The importance of these areas of research is demonstrated by their presence as extraordinary opportunities in cancer research in NCI's Bypass Budget for 2001 and the issuance of special initiatives (see Rare Diseases Research Initiatives). NCI-supported research, conducted at multiple centers throughout the country and by intramural scientists, is leading to rapid advances in these areas.

Neurofibromatosis 2 (NF2)

Neurofibromatosis 2 (NF2) is a rare autosomal dominant disorder characterized by the development of bilateral vestibular schwannomas, other cranial and spinal schwannomas, cranial and spinal meningiomas, and ependymomas. Because spinal tumors are common in NF2, their presence raises issues about appropriate management strategies, because the natural history of NF2-associated tumors may differ from that of their sporadic counterparts. NCI researchers retrospectively reviewed the spinal magnetic resonance images of 49 NF2 patients and counted intramedullary tumors and intradural extramedullary nerve sheath tumors (NSTs) and meningiomas. Thirty-one patients (63%) had spinal tumors; 26 (53%) had intramedullary tumors, 27 (55%) had extramedullary tumors, and 22 (45%) had at least one tumor of each type. Only 3 patients (12%) with intramedullary tumors versus 16 patients (59%) with extramedullary tumors ever reported surgery for the respective tumor type. These results, which suggest that many intramedullary tumors associated with NF2 exhibit more benign behavior than sporadic intramedullary tumors or NF2-associated extramedullary tumors, have implications for long-term management. Among a subset of 37 NF2 patients with known germ line mutations, NCI investigators found that those with nonsense and frameshift mutations were more likely to have intramedullary tumors and significantly higher mean numbers of spinal tumors, intramedullary tumors, and NSTs than patients with other types of mutations. These results suggest that patients with nonsense and frameshift mutation have more spinal manifestations of NF2 than patients with other types of mutations and that genotype-phenotype correlations may extend to specific categories of spinal tumors.

Recent Scientific Advances in Rare Diseases Research: Cancer Prevention and Control

Within the past 2 years, NCI restructured and strengthened its programs in cancer prevention and control. In the aftermath, NCI has developed and implemented a burst of new initiatives in chemoprevention, behavior modification, cancer surveillance, and health communication (see Rare Diseases Research Initiatives). Advances in cancer prevention and control are critical to reducing the cancer burden, especially because they focus heavily on translating new basic research findings in cancer biology and cause into effective interventions.

Vaccines To Prevent Cervical Cancer

Papillomaviruses (PVs) infect the epithelia of animals and humans, where they generally induce benign proliferation at the site of infection. However, a strong association exists between malignant progression of human genital lesions and certain human PV (HPV) types, most frequently HPV-16. NCI investigators have generated viruslike particles (VLPs) for HPV-16 and other PVs. Parenteral injection of purified VLPs has been shown to induce high titers of neutralizing antibodies and protection from experimental challenge in animal models. Based on these results, these investigators have validated GMP-grade VLPs and have recently completed an HPV-16 VLP vaccine phase 1 clinical trial. Vaccines, even those vaccinated in the absence of adjuvant, produced high titers of HPV-16 pseudovirion neutralizing antibodies and reported only minor side effects. The long-term objectives of this study are to conduct a phase 2 trial for current VLP vaccine and develop alternative vaccine candidates.

Recent Scientific Advances in Rare Diseases Research: Cancer Treatment

FY 1999 was another banner year for advances in cancer treatment by intramural NCI scientists and by extramural scientists supported by NCI.

Preclinical Drug Development

The NCI Drug Developmental Program continues screening new synthetic and natural compounds for antitumor activity with the automated cancer cell line screen. Approximately 77,000 defined chemical structures have been evaluated since the screen became operational in April 1990. More than 7,500 compounds have demonstrated in vitro antitumor activity, of which 3,900 agents were selected for in vivo evaluation for assessment of therapeutic activity. Obviously, there are more compounds to test/develop than current resources allow. In the past year, the decisionmaking process supporting the development of new drugs has been reformed. In the place of the Decision Network, the Drug Development Group (DDG) now incorporates extramural review of proposed activities. A complete description of this process is available on the Development Therapeutics Web site (http://dtp.nci.nih.gov). Including vaccines, other biologicals, and chemotherapeutic agents, a total of 26 agents are in DDG level 2A (small animal testing), 3 agents are in DDG level 2B (large animal/primate testing), and 20 are in DDG level 3 (ready for human testing subject to obtaining investigational new drug (IND) approval. Table 1 provides a listing of the agents in the DDG process. As the agents move through the different levels of the decision process, the level of financial commitment by NCI increases.

To further expedite the movement of academic discoveries from the laboratory to proof of principal clinical trials, NCI initiated a program called Rapid Access to Intervention Development (RAID) in 1998. RAID makes the following available to the academic research community on a competitive basis:

1. The steps in preclinical development that are necessary to convert a new molecule into a drug candidate suitable for clinical testing and that are generally not otherwise available to academic investigators who lack a corporate partner. These steps include GMP synthesis, formulation, rangefinding, and IND-directed toxicology and pharmacology.
2. Planning clinical trials.
3. Regulatory affairs, so that the requirements of the FDA may be satisfied by any investigator who seeks to put a new molecule into the clinic.
4. Filing of IND and direct study sponsorship by NCI, where indicated.

As of May 2000, 120 applications have been received, 40 applications were successful and received NCI support, and 5 applications are awaiting review. A description of the successful applicants and the projects can be found at http://dtp.nci.nih.gov/docs/raidwin1.html. A listing of RAID projects pertaining to rare diseases is found in table 4.

Clinical Research

Combined Treatments for Hodgkin's Disease

The NCI-supported Southwest Oncology Group (SWOG) completed a clinical trial in patients with early stage Hodgkin's disease in which patients were randomized to receive either total lymphoid irradiation or three courses of doxorubicin and vinblastine followed by total-body irradiation. The study was closed early because of a significantly prolonged disease-free survival in the combined modality arm. The Eastern Cooperative Oncology Group (ECOG) recently completed a pilot study of the Stanford V regimen with radiation therapy in 47 patients with high-risk, advanced-stage Hodgkin's disease. With a median followup of 4.8 years, 45 patients are alive, and 40 have been disease free continuously. The estimated freedom from progression was 87% at 2 years and 85% at 5 years. Overall survival was 96% at 2 and 5 years. On this basis, an intergroup study comparing doxorubicin, bleomycin, vinblastine, and dacarbazine with the Stanford V regimen has been initiated.

Improvements in Treatment of Head and Neck Cancers

Two cooperative group trials were reported this year that showed incremental improvement in therapy for locally advanced cancers of the oral cavity, oropharysquamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx were randomized to (1) standard fractionation radiation (SFX) at 2 Gy/fx per day, 5 days per week, to a total dose of 70 Gy/35 fx in 7 weeks; (2) hyperfractionation (HFX) at 1.2 Gy/fx twice daily ( 6 h apart), 5 days/week, to a total dose of 81.6 Gy/68 fx in 7 weeks; (3) accelerated fractionation with split (AFX-S) at 1.6 Gy/fx twice daily ( 6 h apart), 5 days per week, to a total dose of 67.2 Gy/42 fx in 6 weeks, including a 2-week rest after 38.4 Gy; or (4) accelerated fractionation with concomitant boost (AFX-C) at 1.8 Gy/fx per day, 5 days per week, to large field +1.5 Gy/fx per day to boost field given 6 h after treatment of the large field for the last 12 treatment days, to a total dose of 72 Gy/42 fx in 6 weeks. A total of 1,073 patients were analyzable. The results showed that both hyperfractionation and accelerated fractionation with concomitant boost resulted in better 2-year local, regional control (54.4% and 54.5%, respectively) than standard fractionation (46%) and accelerated fractionation with a split (47.5%) (p < .05). Acute toxicity was increased in all experimental arms compared with standard treatment. However, late toxicity, although also increased in the experimental arms, was mostly transient. There was no difference in overall survival. This is the largest randomized trial of altered fractionation radiation therapy of locally advanced head and neck cancer. The results suggest that total dose and treatment duration are important for local control of these cancers. However, the lack of effect on overall survival and the increased toxicity leave several questions unanswered, such as the benefit of altered fractionation radiation alone versus the efficacy of concomitant radiation with systemic anticancer therapy, which is commonly used at head and neck cancer treatment centers. Because head and neck cancer tends to recur locally, aggressive local treatment appears warranted. Studies are under way to assess the feasibility of combining chemotherapy with altered fractionation radiation in the treatment of this disease.

In the second trial, 295 patients with locoregionally advanced, unresectable squamous cell carcinoma of the head and neck were randomized to (1) standard fractionated radiation therapy, (2) standard fractionated radiation with concurrent cisplatin, or (3) split-course radiation therapy with concurrent cisplatin plus 5-fluorouracil. Initial results show that toxicity is increased but acceptable in the chemotherapy plus radiation therapy arms; projected median 2-year Kaplan-Meier survival was 30% for arm 1 versus 43% for arm 2 and 40% for arm 3. Median survivals for arms 1, 2, and 3 are 12.6, 19.1, and 14 months, respectively. This trial showed that addition of high-dose cisplatin to standard radiation therapy can be safely administered and significantly improves survival. Taken together, these two trials indicate that optimal treatment for regionally advanced squamous carcinoma of the head and neck in patients with good performance status and good medical health consists of either altered fractionation radiation alone or standard radiation with concomitant cisplatin. Future studies will address improvements to these regimens for both local control and survival.

Immunotherapy for Melanoma

In an interesting confluence of laboratory and clinical medicine, tumor-infiltrating lymphocytes (TIL ) obtained from patients with melanoma have been used to clone the genes encoding the antigens recognized by these TILs. TILs have been identified that can recognize unique cancer antigens on murine and human cancers, including melanoma, breast cancer, colon cancer, and lymphoma. The MHC-restricted recognition of human cancer antigens was detected by assaying panels of HLA-typed target cells and by transfection into target cells of genes encoding the appropriate HLA specificities. In clinical trials of TIL administration, 36% of patients with metastatic melanoma underwent objective cancer remission. TIL trafficked to and accumulated in cancer deposits in patients responding to this unique approach to cancer immunotherapy. With TILs capable of mediating in vivo regression, multiple genes encoding tumor antigens have been identified. A series of clinical studies has been performed with these genes and gene products for the immunotherapy of patients with metastatic melanoma. Twenty-three patients have been immunized with the immunodominant MART-1 peptide, and 27 patients have been immunized with one of three gp100 immunodominant peptides. In studies of peptides containing individual amino acid substitutions designed to increase MHC binding, two modified peptides from the gp100 molecule-gp100:209-217(210M) and gp100:280-288(288V)-were identified that had far greater in vitro immunogenicity than the native peptides. Ninety-one patients have been treated in a clinical trial using immunization with the modified gp100:209-217(210M) peptide either alone or with IL-2, IL-12, or granulocyte macrophage colony-stimulating factor (GM-CSF). Immunization with this peptide alone was capable of generating high levels of antipeptide and antitumor precursors in peripheral blood. In a pilot trial of 31 patients, 42% receiving this modified peptide plus IL-2 have shown objective cancer responses.

Therapy for HTLV-I-Associated Adult T-Cell Leukemia

IL-2 receptor- (IL-2R ) is not expressed in normal cells, whereas it is expressed in individuals rejecting allografts, in abnormal T cells in patients with select autoimmune disorders, and in certain leukemias and lymphomas. In particular, IL-2R is strongly expressed by the malignant T cells of patients with the previously universally fatal adult T-cell leukemia (ATL) that is caused by the human retrovirus HTLV-I. ATL is an aggressive leukemia/lymphoma of mature T cells associated with hypercalcemia and immunodeficiency. No form of chemotherapy has prolonged the survival of these patients, who have a median survival of only 9 months. However, NCI investigators introduced different forms of IL-2R-directed therapy, including unmodified antibodies to IL-2R (anti-Tac), humanized anti-Tac, and this antibody armed with toxins or a- and b-emitting radionuclides. Partial or complete remissions were induced in from 30% to more than 50% of ATL patients who received unmodified antibodies or antibodies armed with yttrium-90, respectively. Furthermore, humanized anti-Tac (Daclizumab) was of value as part of a regimen to reduce renal transplant rejection, leading to FDA approval.

Shedding Light on Risks of Bone Marrow Transplantation

A multi-institutional collaborative study was conducted to examine the incidence and risk factors of posttransplant lymphoproliferative disease (PTLD) among 18,014 patients who underwent allogenic bone marrow transplantation. Incidence was highest 1 to 5 months posttransplant, followed by a steep decline among survivors of 1 year or more. Risk of early-onset PTLD was strongly associated with unrelated or HLA-mismatched related donor, T-cell depletion of donor marrow, and use of anti-thymocyte globulin or anti-CD3 monoclonal antibody for prophylaxes or treatment of acute GVHD. Late-onset PTLD was associated only with extensive chronic GVHD. These findings indicate that altered immunity and T-cell regulatory mechanisms are predictors of both early-onset and late-onset PTLD.

Rare Diseases Research Initiatives

NCI uses program announcements and RFAs to announce special initiatives. These initiatives range from soliciting for specialized networks and centers and encouraging research using molecular approaches in tumor/biomarker classification and identification to encouraging and supporting clinicians and minorities in clinical research.

Evaluation of Methods for More Accurate Diagnosis and Prognosis for Cervical Cancer

Despite recognizable inaccuracies in staging for cervical cancer and the need for many conventional and invasive procedures, modern cross-sectional imaging has not been incorporated into routine evaluation. The American College of Radiology Imaging Network (ACRIN), NCI's cooperative group for imaging studies, has initiated a clinical trial that will compare clinical staging to pretreatment evaluation by computed tomography and MRI in 465 women to establish the most accurate pretreatment staging, the most accurate pretreatment assessment of morphological tumor prognostic factors, and a pathway to decreased use of invasive tests and to design diagnostic test algorithms that consider both benefits and costs of pretreatment evaluation of cervical cancer. The standard of reference for each test performance will be surgical pathology with lymph node sampling or dissection.

Evaluation of Screening Methods for Ovarian Cancer

The PLCO ( prostate, lung, colorectal, and ovarian) Screening Trial, which is being carried out among 152,000 subjects at 10 screening centers nationwide, is designed to evaluate methods for the early detection of PLCO cancers. Enrollment is almost completed. Efforts are being made to have the study population reflect the general population racially and ethnically. Men will be screened yearly for prostate and lung cancers and women for ovarian and lung cancers. All participants in the screening group will be screened at their initial and third yearly visits for colorectal cancer. The control group of participants will receive routine medical care. Both groups will be followed for at least 10 years to determine the effects of screening for the four sites on cancer mortality.

Identification and Evaluation of Markers for Early Detection and Risk Assessment

The Early Detection Research Network (EDRN) is a national network of academic and industry investigators with expertise in laboratory and clinical sciences, biostatistics, informatics, and public health issues. The goal is to identify and evaluate biomarkers and technologies for earlier detection and assessment of risk. The Biomarkers Developmental Laboratories have been funded to identify and develop biomarkers for earlier cancer detection and risk assessment, and the Clinical/Epidemiology Centers have been funded to conduct clinical and epidemiological research on the wide application of biomarkers.

Screening Drugs To Prevent Cancer

Significant effort has been devoted to new in vitro and animal model assays that evaluate activity against specific genetic and molecular targets associated with carcinogenesis. Some of the molecular targets are oncogenes and others are molecules on signal transduction pathways affecting cell growth and proliferation. For example, the following assays were added to NCI's chemoprevention testing program: (1) ras oncogene inhibition as measured by protein farnesylation inhibition (using rat brain farnesyl protein transferase), and (2) epidermal growth factor receptor (EGFR) inhibition (measured as inhibition of EGFR from A31 human epidermoid carcinoma cells in phosphorylation of angiotensin).

Clinical Evaluation of Drugs To Prevent Cancer

NCI's Chemoprevention Program is sponsoring 12 phase I and more than 80 phase II and III trials. Several agent classes are represented in the phase II and III trials, such as retinoids, calcium, anti-inflammatories (e.g., aspirin, sulindac, COX-2 inhibitors, and corticosteroids), antiestrogens/antiandrogens, and antimutagens (e.g., dithiolthiones). Agents in phase I trials include indole-3-carbinol, the combination of oltipraz and N-acetyl-l-cysteine, curcumin, phenethyl-isothiocyanate, perillyl alcohol, the combination of selenomethionine and vitamin E, soy isoflavones, tea polyphenols, and lycopene.

Management of Cervical Abnormalities

The NCI Cervical Cancer Screening and Triage Study is a clinical trial designed to determine the optimal management of minor and low-grade cervical cytological abnormalities, taking into account recent knowledge of the role of HPV in cervical cancer. Recruitment of 5,000 women was completed this year.

Rare Diseases-Related Program Activities

Meetings

In 1999, NCI jointly sponsored the scientific meeting Organ Preservation Therapies for Cancers of the Oropharynx and Hypopharynx with NIH/ORD. In 2000, NCI and ORD will jointly sponsor the following scientific meetings: (1) Workshop on Genetic Susceptibility to Urologic Cancers, (2) New Insights into the Biology of Waldenstrom's Macroglobulinemia and New Treatment Options, (3) Workshop on Gastrointestinal Stromal Tumor Markers, (4) Innovative Strategies for Screening Women at Increased Genetic Risk of Ovarian Cancer, and (5) Workshop on Radiation-Related Thyroid Cancer and Other Rare Thyroid Diseases Among Persons Exposed as Children to Fallout From the Semipalatinsk Nuclear Test Site in Northeastern Kazakstan.

NSC Number	Decision Network IIA	NSC Number	Decision Network III
609395	Halichondrin B
684682	Saporin immunoconjugate: BU12-saporin	696081	Humanized CC49 CH2
684683	Saporin immunoconjugate: OHT10-saporin	700553	Discreet
684684	Saporin immunoconjugate: 4KB128-saporin	683864	Rapamycin analog
710305	Discreet Monoclonal antibody	603573	HeFi-1 Anti-CD30
680718	Nitidine-like compound	710084	Discreet
710464	Discreet	710085	IDEC-Y2B8 Radiolabeled Anti-CD20 antibody
701315	Anti-HER2 immunoliposomes	710427	Discreet
678516	18F-FMAU	639829	Dimethyl benzoylphenylurea
678515	FAU	713219	SGN-00101 (Hsp-E7)
703940	Angiostatin	702827	SU6668
703939	RFB4-onconase	713763	BMS-275291
705701	9-nitro-paullone	714373	LY353381-HC1
709399	Synerlip-p53	715055	ZD1839
690073	Discreet	659853	2-Methoxyestradiol
694501	Discreet	715969	CAMPATH-1H
713205	Halofuginone	716051	STI571
696823	Discreet	716711	Epratuzumab (hLL2)
696824	Discreet	707299	Recombinant Fowlpox(rF)-GM-CSF
696825	Discreet	716976	BNP7787
696826	Discreet	711007	HuM291 (humanized anti-CD3 MoAb)
707016	Discreet
707017	Discreet
707018	Discreet
Decision Network IIB
712392 LB42908
706995 MS-275
698215 R(+)XK469

Agent	Drug Company	Agreement
17-lA	Glaxo Wellcome	CTA
2-Methoxyestradiol and Analogs	Entremed, Inc.	CRADA
280-446	Novartis	CTA
506U78	Glaxo Wellcome	CTA
776C85/5-FU	Glaxo Wellcome	CTA
9-Amino-Camptothecin	Idec Pharmaceuticals	CRADA
9-cis-Retinoic Acid	Ligand	CTA
AE-941	Aeterna	CTA
ALVAC-IL-12	Pasteur-Merieux Con FR	CTA
Antigen Genes Formulated for Delivery in a Dermal Powderject XR Gene Delivery Device	Powderject	CTA
Arsenic Trioxide	Polarx	CRADA-LOI
Bizelesin	Pharmacia/Upjohn, SPA	CTA
BUDR	Neopharm	CTA
C2B8 (Rituximab)	Idec Pharmaceuticals	CRADA
CI-958	Parke-Davis	CRADA
COL-3	Collagenex	CRADA
Decitabine	Pharmachemie	CRADA
Depsipeptide (FR901228)	Fujisawa	CTA
Detox Adjuvant/Detox PC	Ribi Immunochem Res.	CTA
Dolastatin 10	Knoll	CTA
DX-52-1	Kyowa Hakko Kogyo	CTA
EMD 121974	Merck Kgaa	CRADA
Endostatin	Entremed, Inc.	CRADA
F-dda	US Bioscience	CRADA
Fenretinide	RW Johnson Pharm	CTA
FLavopiridol	Hoechst India Ltd.	CTA
FLT3	Ligand Immunex	CTA
G3139	Antisense Project Genta	CRADA-LOI
Gadolinium	Texaphyrin Pharmacyclics	CRADA
Gemcitabine	Lilly	CTA
GM-CSF	Immunex	CTA
Herceptin	Genentech	CRADA-LOI
Herceptin	Genentech	CTA
Homoharringtonine	American Bioscience Inc.	CRADA
IL-12	IL-12 Partners	CRADA
IL-12	IL-12 Partners	C
IL-2	Chiron Corporation	CTA
Iododoxorubicin	Pharmacia/Upjohn, SPA	CTA
Irinotecan	Pharmacia/Upjohn	CTA
KRN5500	Kirin	CTA
Lutetium	Texaphyrin Pharmacyclics	CRADA
MGI 114	Mgi Pharma	CTA
Mitoguazone	Ilex	CTA
MTP-PE	Jenner Technologies	CTA
O6-BG	Pacific Pharmaceuticals	CRADA
Onyx-015	Onyx	CRADA
Ovaliplatin	Sanofi-Winthrop	CRADA
P53 Adenovirus	Gencell/RPR	CRADA
Perifosine (D-21266)	Asta Medica	CRADA-LOI
PS-341	Proscript	CRADA
PSC-833	Novartis	CTA
QS-21	Cambridge Biotech	CTA
R115777	Janssen Pharmaceutica	CTA
Rebeccamycin Analog	Bristol-Myers Squibb	CTA
Rhizoxin	Fujisawa	CTA
Rhumab VEGF	Genentech	CTA
Sandostatin	Novartis	CRADA-LOI
Sarcnu	Panasci	CTA
SC-55494	Searle	CTA
Smart 1D10 (HU1D10)	Protein Design Labs, Inc.	CTA
Sodium Phenylacetate/Sodium Phenylbutyrate	Targon	CTA
SU5416	Sugen, Inc.	CTA
Suramin	Parke-Davis	CRADA
Taxol	Bristol-Myers Squibb	CTA
Taxotere	Rhone-Poulenc Rorer	CRADA
Thalidomide	Celgene Corporation	CTA
Thalidomide	Entremed, Inc.	CTA
Tiripazamine	Sanofi-Winthrop	CTA
Tomudex	eneca	CRADA
Topotecan Hydrochloride	Smithkline Beecham	CTA
Tumor Necrosis Factor-	Boehringer Ingelheim	CTA
UCN-01	Kyowa Hakko Kogyo	CTA

Cytoxic Agents		Biological Agents
Phase I	Phase II	Phase I	Phase II
17-AAG	Amino-camptothecin	ALVAC-B7.1	Anti-idiotype-KLH lymphoma vaccine
Arsenic trioxide	Bryostatin 1	ALVAC-CEA-B7.1	Carboxypeptidase G2
Benzylguanine	BSO	ALVAC-IL-12	cis-Retinoic acid
Bizelesin	CAI	Anti-Tac (Fv)-PE38 immunotoxin	IFN receptor
COL-3	Cl-958	BL22 immunotoxin	IL-4
Compound 506U	Cl-980	Carcinoembryonic antigen peptide vaccine	IL-21TIL
Cordycepin/pentostatin	Compound 776C85 C	EA vaccinia vaccine	MoAb CC49
Depsipeptide	Dolastatin 10	E1B-attenuated adenovirus	MoAb C2B8
EF5	Fenretinide	FLT3 ligand	MoAb OKT3
Iododoxorubicin	Flavopiridol	Fowlpox-PSA vaccine	MoAb14.18 chimeric
KRN5500	Perillyl alcohol	gp100 DNA vaccine
N-Monomethyl-l- arginine	Phenylacetate	gp100 Melanoma vaccines
Phenylbutyrate	PSC 833	HER-2/Neu peptide vaccine
Quinocarmycin analog	Pyrazoloacridine	HIV 1 vaccine
Rebeccamycin analog	Pyrazine diazohydroxide	HPV E6 and E7 vaccine
UCN-01	Temozolomide	HPV E7 lipopeptide vaccine
	Thioguanine (IV)	IL-12
	Tirapazamine	Immunotoxin ERB-38
		Immunotoxin LMB-1
		Immunotoxin LMB-7
		Immunotoxin LMB-9
		MART-1 melanoma vaccines
		MoAb anti-VEGF
		MoAb A27.15 and E2.3
		MoAb B3
		MoAb CC49-9OY
		MoAb humanized Her2
		MoAb T cell 3A1, 95-5-49, 95-6-22
		MOV-18 chimeric T-cell receptor
		P53 adenovirus vector
		P53 and RAS peptide vaccine
		Pediatric sarcoma peptide vaccines
		PSA vaccinia vaccine
		RAS peptide vaccine
		Vaccinia-PSA vaccine
		Vaccinia-MUC1 vaccine
		VHL peptide vaccine

Compound NSC	Name	Disease	Investigator
RAID Compounds
710296	C-MYB antisense Oligodeoxynucleotide	Acute myelocytic Leukemia	Alan Gewirtz, University of Pennsylvania, School of Medicine
710295	Bradykinin antagonist	Small cell and non-small cell lung	Paul Bunn, University of Colorado Cancer Center
710292	Lipopeptide	Cytomegalovirus	Don Diamond, City of Hope Medical Center
354258	8-Chloro-adenosine	Multiple myeloma	Steven Rosen, Northwestern University, Lurie Comprehensive Cancer Center
710293	FGR-replication	competent adenovirus Prostate	Svend Freytag, Henry Ford Health System
711516	Chimerized antiamyloidosis MoAb	AL amyloidosis	Alan Solomon, University of Tennessee
711517	Shed polyvalent antigen vaccine	Melanoma	Jean-Claude Bystryn, New York University Medical Center
711293	TfRscFv-anti-transferrin receptor scantibody	Prostate	Esther Chang, Georgetown University, Lombardi Cancer Center
711295	MoAb 216 (VH4-34) Anti-HuBlymphocyte antibody	Lymphoma	Nelson N. H. Teng, Stanford University
711518	Allogenic pancreatic tumor vaccine	Pancreas	Elizabeth M. Jaffee, Johns Hopkins University
711519	IGF-1R antisense oligodeoxynucleotide	Glioma	Robert Aiken, Thomas Jefferson Medical College
714597	Imexon	Multiple myeloma	Robert Dorr, University of Arizona, Arizona Cancer Center
113090	Betulinic Acid	Multiple myeloma	Tapas Das Gupta, University of Illinois at Chicago
650378D	Spongistatin 1	Melanoma, ovary	George Pettit, Arizona State University, Cancer Research Institute
734551 714503	Fenretinide plus Safingnol	Neuroblastoma, small cell lung, prostate, pancreas, acute leukemias	C. Patrick Reynolds, University of Southern California School of Medicine
715815	Chimeric anti-CD54 MoAb (UV3)	Myeloma	Ellen Vitetta, University of Texas, Southwestern Medical Center
715816	Tropism-modified adenoviral vector	Ovary	Glenn Peters, University of Alabama, Comprehensive Cancer Center
717904	Immucillin-H	T-cell lymphoma	Vern Schramm, Albert Einstein College of Medicine
7365	6-Diazo-5-oxo-l-norleucine	Neuroendocrine	Håkan Örlefors, Uppsala University Hospital, Sweden
RAID Exception Compound
713204	PDX Anti-fol	Non-small cell lung cancer	F. Sirotnak; Memorial Sloan-Kettering Cancer Center