Sorafenib (Nexavar®) Significantly Improves the Length of Time Before Breast Cancer Worsens: Results From First, Large Randomized Trial

Approximately 30 studies evaluating the use of sorafenib (Nexavar®, Bayer Healthcare Pharmaceuticals/Onyx Pharmaceuticals)tablets across tumor types – as a single agent or in combination with other therapies – were presented at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin.

“The presentations at the ECCO/ESMO conference continue to build on our large body of data in unresectable liver cancer and advanced kidney cancer where sorafenib has a proven track record,” said Dimitris Voliotis, Vice President, Global Clinical Development Oncology. “Additionally, we are very enthusiastic about the presented Phase 2 studies evaluating the safety and efficacy of sorafenbib in other tumor types, including breast and thyroid cancers.”

One of the first of a series of trials to investigate the use of sorafenib – a targeted anti-cancer drug – for the treatment of advanced breast cancer has found that if it is combined with the chemotherapy drug, capecitabine (Xeloda®, Roche, Basel, Switzerland), it makes a significant difference to the time women live without their disease worsening.

Principal investigator of the study, Professor José Baselga told his audience: “This is the first, large, randomized study that demonstrates significant clinical activity of sorafenib in breast cancer when given in combination with chemotherapy. Our results showed that patients who received sorafenib plus capecitabine had a 74% percent improvement in the time they lived without their disease worsening compared to those who received the chemotherapy alone. This is a very positive study and the magnitude of the benefit is such that it suggests that this agent will be an important addition to our therapeutic armory in breast cancer.”

Sorafenib is a potent multi-kinase inhibitor, which works by interfering with the growth of cancer cells and slowing the growth of new blood vessels within the tumor. Until now, it has only been used in the treatment of kidney and liver cancer.

Prof Baselga, who is head of the oncology department at Vall d’Hebron University Hospital (Barcelona, Spain), president of ESMO (European Society for Medical Oncology) and a member of the ECCO (European CanCer Organization) executive committee, and his colleagues in Spain, France and Brazil enrolled 229 patients with locally advanced or metastatic breast cancer in the double-blind, randomized phase II clinical trial between June 2007 and December 2008. They randomized the patients to receive capecitabine (1000 mg/m2 pill taken twice daily for 14 of every 21 days) and a placebo (114 women), or capecitabine and sorafenib (400 mg pill taken twice daily continuously) for 115 women.

The very first results from the trial only became available in time for the ECCO 15 – ESMO 34 congress, and they show that the average progression free survival (the time that elapses without the cancer getting worse) was 6.4 months for women on capecitabine and sorafenib compared to 4.1 months for women taking the placebo. It is too early for data on overall survival to be available. The only death that occurred was in the placebo arm of the trial, attributed to the effect of capecitabine. The number of patients discontinuing treatment due to adverse side-effects was nine (8%) in the placebo arm and 15 (13.4%) in the sorafenib arm of the trial.

Prof Baselga said: “The regimen was tolerable and the side-effects were mostly manageable. No new or unexpected side effects were observed with this combination. The fact that this treatment could be taken orally may represent a unique and convenient treatment option for patients with breast cancer.

“This trial is an example of good academia and industry partnership. It was designed and conducted by the Spanish breast cooperative group SOLTI with the participation also of Brazilian and French groups. The trial was fully supported by Onyx and Bayer. Based on the encouraging data from this trial so far, Onyx and Bayer are evaluating various strategies for sorafenib in breast cancer.

“This trial is the first of a series of randomized phase II studies with sorafenib that are currently underway in breast cancer. Based on our results, we believe that the drug shows considerable promise for the treatment of the disease.”

For more information:

• Jose Baselga, M.D., Vall d'Hebron University Hospital in Barcelona, Spain. A double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (PL) when administered in combination with capecitabine (CAP) in patients (pts) with locally advanced (adv) or metastatic (met) breast cancer (BC). Late-breaking abstract 3LBA, Presidential Session III, Wednesday, September 23, 1:30 p.m., Hall 1

Other trial results:

Hepatocellular Carcinoma

• Jean-Luc Raoul, M.D., Centre Eugène Marquis, Rennes, France. Effect of Macroscopic Vascular Invasion (MVI), Extrahepatic Spread (EHS), and ECOG Performance Status (ECOG PS) on Outcome in Patients with Advanced Hepatocellular Carcinoma (HCC) Treated with Sorafenib: Analysis of Two Phase 3, Randomized Double-Blind Trials. Abstract 6621, Poster 309, Wednesday, September 23, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Josep Llovet, M.D., Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain. Efficacy and Safety of Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC): Collective Results from the Phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Asia-Pacific (AP) Trials. Abstract 6519, Poster 13, Tuesday, September 22, 2009, 8 a.m. – 11 a.m., Poster Discussion, 11:15 a.m. – 12:15 p.m., Central Lobby (Outside Hall 3)

Renal Cell Carcinoma

• Joachim Beck, M.D., Johannes-Gutenberg-Universität III. Medizinische Klinik, Mainz, Germany. Final Analysis of a Large Open-label, Noncomparative, Phase 3 Study of Sorafenib in European Patients with Advanced RCC (EU-ARCCS). Abstract 7137, Poster 150, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Hideyuki Akaza, M.D., Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan. Efficacy and Safety of Long-term Use of Sorafenib: Final Report of a Phase II Trial of Sorafenib in Japanese Patients with Unresectable/Metastatic Renal Cell Carcinoma. Abstract 7147, Poster 160, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Ronald M. Bukowski, M.D., Cleveland Clinic Taussig Cancer Center, Cleveland, OH. Efficacy and Safety of Sorafenib in Patients with Advanced Clear-Cell Renal-Cell Carcinoma (RCC) with Bone Metastases: Results from the Phase III TARGET Study Abstract 7130, Poster 143, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Dirk Jäger, M.D., National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany. PREDICT (Patient characteristics in REnal cell carcinoma and Daily practICe Treatment with Nexavar) Global Non-interventional Study: First interim results. Abstract 7128, Poster 141, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1

Thyroid Cancer

• Marcia Brose, M.D., Ph.D. Department of Medicine, Division of Hematology/Oncology and Department of Otorhinolaryngology: Head and Neck Surgery, Abrahamson Cancer Center of the University of Pennsylvania, Philadelphia, PA, U.S.A. Completion of a Phase II study of sorafenib for advanced thyroid cancer. Late-breaking poster 51LBA, Poster 276, Tuesday, September 22, 11 a.m. – 1:00 p.m. Hall 14.1

Highlights of Prescribing Information:

• Sorafenib (Nexavar ®)
• Capecitabine (Xeloda®)

Also read these Pubmed Abstracts:

• Higgins MJ, Forastiere A, Marur S. New directions in the systemic treatment of metastatic thyroid cancer. Oncology (Williston Park). 2009 Aug;23(9):768-75.
• Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs. 2009 Aug;20(7):616-24.
• Hill KL Jr, Lipson AC, Sheehan JM. Brain magnetic resonance imaging changes after sorafenib and sunitinib chemotherapy in patients with advanced renal cell and breast carcinoma. J Neurosurg. 2009 Sep;111(3):497-503.
  Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I. Tyrosine kinase blockers: new hope for successful cancer therapy Anticancer Agents Med Chem. 2009 Jan;9(1):66-76. Review.
• Schraml C, Schwenzer NF, Martirosian P, Bitzer M, et al. Diffusion-weighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results. AJR Am J Roentgenol. 2009 Oct;193(4):W301-7.
• Sugawara M, Geffner DL, Martinez D, Hershman JM. Novel treatment of medullary thyroid cancer. Curr Opin Endocrinol Diabetes Obes. 2009 Oct;16(5):367-72.

XL184 shows substantial activity in Patients with Previously Treated Glioblastoma Multiforme and Medullary Thyroid Cancer

Results from the ongoing phase II trial of XL184 demonstrates substantial activity in patients with previously treated progressive or recurrent glioblastoma multiforme (study XL184-201). Data of the ongoing trial was presented during the 45th annual meeting of the American Society of Clinical Oncology (ASCO). XL184 has exhibited dose-dependent tumor growth inhibition and tumor regression in a variety of tumor models, including breast cancer, colon cancer, medullary thyroid cancer , non-small cell lung cancer, and glioblastoma. Additional research now shows that treatment with XL184 at a dose of 175 mg PO qd results in potent inhibition of glioblastoma multiforme (GBM).

XL184 (BMS-907351) is a potent, orally administered, small molecule inhibitor of receptor tyrosine kinases. The compound also inhibits MET, a receptor tyrosine kinase that plays a key role in cellular proliferation, migration, and angiogenesis. MET is mutationally activated in some tumor types, such as hereditary and sporadic papillary renal cell carcinoma and some head and neck cancers. More frequently, MET is either over-expressed or activated in the absence of mutation in glioblastomas, breast carcinomas, some gastric cancers, and other solid tumors. MET amplification has been demonstrated in some NSCLCs.

VEGFR2 and RET
Overexpression of MET and vascular endothelial growth factor receptor-2 (VEGFR2), as well as the ligands which activate these receptors, has been shown to correlate with poor prognosis in glioblastoma multiforme, which is the most common and most aggressive form of brain tumor in humans, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors, and occurs in only 2–3 cases per 100,000 people in Europe and North America.

In addition, phosphorylated RET has been described in some cases of glioblastoma multiforme. Expression of VEGF has been observed in a variety of cancers and has been associated with prognostic significance. Targeting the VEGF receptor has been recognized as a potential anti-cancer strategy in multiple tumors. Dual targeting of MET and VEGFR2 blocks two of the major mechanisms tumors use to overcome hypoxia. Activated RET is involved in cell signaling cascades that regulate cell proliferation, migration, differentiation, and survival. RET is mutationally activated in papillary thyroid cancer (PTC) and in both familial and sporadic forms of medullary thyroid cancer (MTC).

Development of XL184
Exelixis Inc. (210 East Grand Avenue, P.O. Box 511, South San Francisco, CA 94083-0511 phone (650) 837-7000,fax (650) 837-8300), a biotechnology company focusing on the development of compounds targeting multiple receptor tyrosine kinases simultaneously as well as components of key components of downstream signaling pathways that play important roles in cancer and metabolic diseases, develops XL184 with Bristol-Myers Squibb Company (BMS), a global biopharmaceutical company.

The companies are currently conducting multiple clinical studies for XL184, in glioblastoma multiforme (GBM) and medullary thyroid cancer (MTC). John De Groot, MD, of The MD Anderson Cancer Center, and an investigator on the Phase 2 glioblastoma-trial, presented data during a poster session during the ASCO meeting.

The exploratory study evaluated the safety, tolerability and clinical activity of XL184 at a continuous daily dose of 175 mg in patients with previously treated glioblastoma multiforme. To date, 46 patients who make up the intent to treat (ITT) population have been enrolled in the trial, including 30 (65%) in first relapse and 16 (35%) in second or third relapse. Importantly, the trial did not exclude patients previously treated with an antiangiogenic agent.

The tumor response, as determined by an independent radiology facility (IRF), using MacDonald criteria were reported. By ITT analysis, 7 of 35 (20%) of the antiangiogenic naïve patients had a confirmed partial response. The overall rate of response in all patients, including the refractory population of previously treated patients with an antiangiogenic therapy, was 15%. The median duration of response by IRF was 2.9 months (range = 1.9-8.6 months). In an exploratory analysis, among 35 patients with at least one post baseline MRI scan, 12 (34%) had tumor shrinkage ≥50% as their best response as determined by investigator, including 1 patient who had received prior antiangiogenic therapy.

The efficacy evaluable population was defined as patients having received at least 1 dose of XL184 and either had at least 1 post-baseline tumor assessment per investigator or failed to return for any tumor assessments because of death or clinical determination of progression. In the anti-angiogenic naïve population, 7 of 31 (23%) of efficacy evaluable patients had a confirmed partial response by IRF. The 6-month progression-free survival (PFS) rate in patients receiving no prior antiangiogenic therapy was 23%, with 10 patients censored for PFS at the time of analysis, and the median PFS interval was 3.6 months.

“These initial data from our ongoing glioblastoma multiforme (GBM) program are encouraging, and suggest that XL184 could have utility in this underserved indication,” said Michael M. Morrissey, Ph.D., president of research and development at Exelixis. “We believe that these data support continued evaluation of XL184 in patients with GBM, and we intend to enroll additional patients in this study to better assess the compound’s anti-tumor activity and safety profile in this difficult to treat patient population.”

As of January 6, 2009 all 46 patients were evaluated for safety. At least 1 post-baseline tumor assessment at 4 weeks was available for 26 pts. Of these, 17 pts had not received prior therapy with an anti-angiogenic agent, whereas 9 pts had received prior therapy with bevacizumab (n = 6), vandetanib (n = 2), or VEGF-TRAP (n = 1). Most adverse events were of Grade 1 or 2 severity. The most frequently occurring Grade 3 and Grade 4 adverse events were: fatigue (30%), alanine aminotransferase increase (9%), confusional state (9%), lipase increase (9%), lymphopenia (9%), convulsion (7%), headache (7%), and hypophosphatemia (7%). Adverse events of special interest were: hypertension (all incidences, 39%; Grade 3/4, 7%), palmar-plantar erythrodysesthesia (30%; 7%), bleeding events (28%; 9%), proteinuria (26%; 0%), pulmonary embolism (9%; 7%) and craniotomy wound dehiscence (4%; 2%).

In the study, 87% of patients had a dose interruption of XL184, median average daily dose was 122 mg/day. XL184 will be evaluated at a lower dose of 125 mg daily in order to provide continuous and sustained exposure to the drug in this previously treated glioblastoma population.

Other studies with XL184
Correlative tumor profiling and biomarker evaluation and vascular imaging data from this trial was also presented in two additional posters in the same poster session. Abstract 2048, entitled “Neurovascular imaging in GBM patients quantifies early physiologic changes after treatment with XL184, an inhibitor of multiple receptor tyrosine kinases: results from a Phase 2 study” was presented by Gregory Sorensen, MD, from the Massachusetts General Hospital, Boston, MA, and abstract 2049, entitled "Correlative tumor molecular profiling and plasma biomarker analysis in a phase 2 study of XL184 in patients with progressive or recurrent glioblastoma multiforme" was presented by Samuel DePrimo, PhD, Exelixis Inc, South San Francisco, CA.

Medullary Thyroid Cancer
The American Cancer Society estimates that Medullary Thyroid Cancer (MTC) accounts for aproximately5% of all thyroid cancers. Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation.

The disease occurs in sporadic and inherited forms (approximately 80% and 20% of MTC, respectively). Patients with the inherited form of medullary thyroid carcinoma (MTC) invariably have an activating mutation in RET in their germline DNA. Activating mutations in RET are also present in the tumor DNA of up to 50% of sporadic MTC patients with no familial history of thyroid cancer. MTC may metastasize to lymph nodes or other organs before it is ever diagnosed. Additionally, MTC does not take up radioactive iodine, which is commonly used to treat other types of thyroid cancers and to diagnose metastases. As a result, MTC is more difficult to treat than other thyroid cancers.

So far, there are no approved therapies for MTC; however, common treatments for MTC include surgery to remove malignant tissue, radiation therapy, and chemotherapy, all of which are associated with potential side effects, some of which may be long-term.

During 2008 annual meeting of the American Society of Clinical Oncology (ASCO) safety and clinical activity data were presented from an ongoing phase 1 trial of XL184 in 69 patients with various solid tumors, including 17 MTC patients evaluable for response. These data showed a disease control rate (percentage of patients with partial responses or prolonged stable disease greater than 3 months) of 100% in the evaluable MTC patients, with 53% of those patients (9 of 17) experiencing partial responses. In this trial, the median duration of partial responses and stable disease for patients with MTC had not yet been reached. Most of the MTC patients in the trial had previously failed other treatments, including tyrosine kinase inhibitors with anti-RET activity, including vandetanib (AstraZeneca, Zactima™, also known as ZD6474), sorafenib (Nexavar®, Bayer/Onyx), or motesanib (Amgen/Takeda) chemotherapeutic agents, immunotherapy, radioactive iodine, and radiotherapy. Patients are now recruited to participate in new and ongoing trials.

ASCO 2009 Abstracts

• De Groot JF, Prados M, Urquhart T, Robertson S, et al. A phase II study of XL184 in patients (pts) with progressive glioblastoma multiforme (GBM) in first or second relapse. J Clin Oncol 27:15s, 2009 (suppl; abstr 2047).
• Sorensen AG, Jenning D, Wang M, Andronesi O, Chen P, et al. Use of neurovascular imaging in GBM patients (pts) to quantify early physiologic changes after treatment with XL184, an inhibitor of multiple receptor tyrosine kinases: Results from a phase II study. J Clin Oncol 27:15s, 2009 (suppl; abstr 2048)\DePrimo S, Wu B, Huang S, Bautista R, Cancilla B, et al. Correlative tumor molecular profiling and plasma biomarker analysis in a phase II study of XL184 in patients with progressive or recurrent glioblastoma multiforme (GBM). J Clin Oncol 27:15s, 2009 (suppl; abstr 2049).
• Fox E, Widemann BC, Whitcomb PO, Aikin A, Dombi E, et al. Phase I/II trial of vandetanib in children and adolescents with hereditary medullary thyroid carcinoma. J Clin Oncol 27:15s, 2009 (suppl; abstr 10014).
• Carr L, Goulart B, Martins R, Keith E, Kell E, et al. Phase II trial of continuous dosing of sunitinib in advanced, FDG-PET avid, medullary thyroid carcinoma (MTC) and well-differentiated thyroid cancer (WDTC). J Clin Oncol 27:15s, 2009 (suppl; abstr 6056)

ASCO 2008 abstracts:

• Salgia R, Sherman S, Hong DS, Ng CS, Frye J, A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 3522). See Poster from EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics, in October 2008 in Geneva, Switzerland.

ASCO 2008 presentations:

• Ravi Salgia, MD, PhD Professor of Medicine, Director, Thoracic Oncology Research Program, University of Chicago Medical Center (Presenter). A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). Abstract No: 3522

Clinical trials:

• Study of XL184 in Adults With Glioblastoma Multiforme (recruiting). The purpose of this study is to evaluate the objective response rate and 6-month progression-free survival rate of XL184 in subjects with recurrent or progressive glioblastoma multiforme. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. Contact: Exelixis Contact Line 1-866-939-4041.
• Phase III Efficacy Study of XL184 in Adults With Medullary Thyroid Cancer (recruiting). The purpose of this research study is to evaluate the progression-free survival (PFS) with XL184 as compared with placebo (an inactive substance) in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). Subjects will be randomized to receive XL184 or placebo in a 2:1 ratio. XL184 is an investigational drug that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. Contact: Exelixis Contact Line 1-866-939-4041 Stanford University School of Medicine, Primary contact: Ruth Lira, (650) 723-1367)
• Study of XL184 in Adults With Advanced Malignancies (ongoing, not recruiting) The purpose of this study is to determine the best and safest dose of XL184 administered orally. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. To determine the highest safe dose, subjects will receive different amounts of the drug. The first group of subjects will receive the lowest dose of XL184. As long as no medically unacceptable side effects are noted, the dose will be increased for the next group. When the maximum tolerated dose (MTD) is reached, at least 20 subjects with Medullary Thyroid Cancer (MTC) will be enrolled to evaluate the effect of XL184 in this population.
• Study of XL184 in Adults With Glioblastoma Multiforme (recruiting) The purpose of this study is to evaluate the objective response rate and 6-month progression-free survival rate of XL184 in subjects with recurrent or progressive glioblastoma multiforme. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration.

Also read PubMed Abstracts:

• He H, Nilsson CL, Emmett MR, Ji Y, Marshall AG, Kroes RA, Moskal JR, Colman H, Lang FF, Conrad CA. Polar lipid remodeling and increased sulfatide expression are associated with the glioma therapeutic candidates, wild type p53 elevation and the topoisomerase-1 inhibitor, Irinotecan. Glycoconj J. 2009 Jun 26. [Epub ahead of print]
• Hottinger AF, Yoon H, Deangelis LM, Abrey LE. Neurological outcome of long-term glioblastoma survivors. J Neurooncol. 2009 Jun 26. [Epub ahead of print]
• Wong ML, Prawira A, Kaye AH, Hovens CM. Tumour angiogenesis: Its mechanism and therapeutic implications in malignant gliomas. J Clin Neurosci. 2009 Jun 23. [Epub ahead of print]
• Adamson C, Kanu OO, Mehta AI, Di C, Lin N, Mattox AK, Bigner DD. Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin Investig Drugs. 2009 Jun 26. [Epub ahead of print]
• Ye L, Santarpia L, Gagel RF. Targeted Therapy for Endocrine Cancer: The Medullary Thyroid Carcinoma Paradigm. Endocr Pract. 2009 Jun 22:1-24. [Epub ahead of print]
• Porterfield JR, Cassivi SD, Wigle DA, Shen KR, Nichols FC, Grant CS, Allen MS, Deschamps C. Thoracic metastasectomy for thyroid malignancies. Eur J Cardiothorac Surg. 2009 Jul;36(1):155-8.
• Cavalheiro BG, Junqueira CR, Brandão LG. Expression of membrane type 1 matrix metalloproteinase in medullary thyroid carcinoma: Prognostic implications. Head Neck. 2009 Jun 17. [Epub ahead of print]
• Kim JM, Chung KW, Kim SW, Choi SH, Min HS, et al. Spurious hypercalcitoninemia in patients with nodular thyroid disease induced by heterophilic antibodies. Head Neck. 2009 Jun 17. [Epub ahead of print]
• Machens A, Lorenz K, Dralle H. Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. J Intern Med. 2009 Jul;266(1):114-25.
• Santarpia L, Ye L, Gagel RF. Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma. J Intern Med. 2009 Jul;266(1):99-113.

More information (General):

• Cuccuru G, Lanzi C, Cassinelli G, Pratesi G, Tortoreto M, et al. Cellular Effects and Antitumor Activity of RET Inhibitor RPI-1 on MEN2A-Associated Medullary Thyroid Carcinoma. JNCI Journal of the National Cancer Institute 2004 96(13):1006-1014. Full Text Article.
• Glioblastoma Multiforme (GBM)
• Carcinomas of the Central and Peripheral nervous system: Glioblastoma multiforme (GBM) - overview.
• Medullary thyroid cancer (MTC)
• New York Thyroid Center (Columbia University Medical Center, Department of Surgery, New York, NY.): Medullary Thyroid Cancer.

Illustrations courtesy of the American Society of Clinical Oncology