publication date: Dec. 13, 2019

Trials & Tribulations

Nobel Prize Award: Impact of Clinical Care?

Ilene Sussman

Ilene Sussman, PhD

Executive director, VHL Alliance


On December 10, 2019, Dr. William G. Kaelin, Jr, Sir Peter J. Ratcliffe, and Dr. Gregg L. Semenza officially received the title of Nobel Laureate in Medicine.

Together, these esteemed researchers provided an understanding of how cells can sense and adapt to changing oxygen levels and how this results in cancer, such as in brain, bladder, breast, colon, ovarian, kidney, and pancreatic cancers.

When cells perceive a lack of oxygen (hypoxia), such as through a defect in the tumor suppressor gene (VHL), the transcription factor, HIF (Hypoxia-Inducible Factor), is not allowed to bind to the VHL protein. HIF is thus protected from degradation.

The accumulation of HIF results in the overexpression of various cellular growth factors (VEGF, PGDF) and a change in the ways cells utilize glucose and generate energy. These changes, in turn, lead to an over production of blood vessels, which ultimately leads to tumorigenesis. Understanding how to overcome the HIF accumulation and the cell’s perception of hypoxia, is key to preventing tumor development and growth.

The work of these three men, particularly Dr. Kaelin, has focused on the VHL gene. In Dr. Kaelin’s research is cause for optimism, not only for the 200,000 people suffering from VHL (von Hippel-Lindau disease) around the world, but also for those facing other cancer diagnoses.



VHL is a genetic form of cancer. VHL patients battle a series of tumors in up to 10 parts of the body throughout their lives. Tumors can develop in the brain, spine, retina, kidney, pancreas, adrenal gland, inner ear, reproductive tract, liver, and lung. Lack of timely intervention can often lead to morbidity and mortality.

As stated by Dr. Kaelin, “When you are studying about von Hippel-Lindau disease, you are not just studying about [the] …. disease … you are also now touching other diseases as well, where we can use the VHL gene to understand what is happening.” As such, the understanding of HIF involvement in tumorigenesis provides hope for the 40% of the world’s population who will be diagnosed with cancer at some point in their lives.

The VHL Alliance (VHLA, has been working for decades with cadres of research professionals and members of the medical community around the world to better understand the VHL gene and its impact on cancer development. The VHL Alliance funds research in numerous areas including work related to that of the newest Nobel Laureates.

Thanks to this research, the FDA has approved eight drugs for the treatment of kidney and breast cancers. These agents target the regulation of cellular growth factors (the downstream consequence of elevated HIF levels).

A HIF inhibitor is currently in clinical trials for VHL and metastatic kidney cancer. Due to our current understanding of HIF, there is reason to believe that this treatment may be effective in other forms of cancer, as well.

The question remains how to overcome the barriers to diagnosis and treatment that do and will continue to impede maximum benefit of this science and resulting medical treatments. This is particularly true when considering rare diseases such as VHL.

VHLA categorizes people with VHL into three groups:

  1. People who are aware and undertake a proactive approach to monitoring their disease and lesion growth in order to achieve a better clinical outcome;

  2. People who disregard their medical condition out of lack of knowledge, anxiety about the unknown, and/or lack of medical options other than surgical intervention;

  3. People who remain undiagnosed, often despite the presence of manifestations and the existence of genetic testing.

A person’s primary physician can be a key influencer in someone’s approach to diagnosis and medical care. Knowledge about the various VHL manifestations along with an understanding of the reasons behind VHL surveillance guidelines are helpful in encouraging a patient to be more proactive in managing their disease.

Understanding the complexity of VHL and the need for the involvement of multiple medical specialties should galvanize clinicians to encourage their patients to seek care at a VHL Clinical Care Center.

In addition, there is hope that advances in science, followed by the development and approval of non-invasive medical options with minimal side-effects, will inspire people to be more proactive in managing their disease.

In VHLA’s experience, a primary factor behind an absence of diagnosis is a lack of information by one’s clinical team. This is no surprise that, due to low prevalence rates, VHL is categorized as one of over 7,000 currently identified rare diseases. It is unrealistic for anyone to know every detail about them all.

Additionally, the medical field generally does not think in terms of outliers (“Zebras” – the analogy in the rare disease world). It is because of this deficiency that actively engaged and highly knowledgeable VHL patients are often forced to educate their medical team.

Utilizing material related to the recent Nobel Prize in Medicine, and in particular, Dr. Kaelin’s Nobel Prize lecture, provides a perfect backdrop to making sure that this prestigious award impacts clinical care.

This Nobel Prize give us an opportunity to educate present and future clinicians and health care providers about VHL and the importance of proactive surveillance as a key to improved outcomes.

This includes the VHL Alliance’s educational materials (,,,,—we also hold educational meetings and work with medical societies in order to increase awareness about VHL disease.


  1. Zhong H, De Marzo AM, Laughner E, Lin M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW. Cancer Research 59, 5830 (1999)

  2. Talks KL, Turley H, Gatter KC, Maxell PH, Pugh CW, Ratcliffe PJ, Harris AL. Am J Pathol 157, 411 (2000)

  3. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane, WS, Kaelin WG. Science 292, 464 (2001)

  4. William G. Kaelin – Nobel Lecture. Nobel Media AB 2019. Mon. 9 Dec 2019.

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