In fact " the Cure for Cancer is in our genes is the " tag line for VHL Alliance (www.vhl.org) said Ilene Sussman, executive director of the VHL Alliance.
"Since VHL patients battle a series of tumors throughout their lives, they are an ideal population for studying tumor growth and identifying ways in which a patient’s lifestyle or environment may affect the progression of the disease,” says Sussman.
And, while von Hippel-Lindau disease is rare, the VHL gene is involved in many other forms of cancer. The new database will include data from patients with several other rare forms of genetic cancer, and could ultimately influence the treatment of many other types of cancer including common forms.
"VHL gene responsible for von Hippel Lindau syndrome. Controls major feeding pipeline of a cell. A mutation in the gene causes cells metabolism to change. Mutations in VHL are also part of the causes of other tumours such as breast, kidney, colon, pancreas etc. As a result, finding a cure for von Hippel Lindau is one step closer to finding cure for many other forms of cancer." said Ilene Sussman
Sunznne Nylender ( ex - director of wellness for vHL Alliance)further explained. vHL is one of the 7000 rare disorders, so most doctors will have no experience with it they may have heard about it in medical school but its difficult to remember until you have seen a patient with vHL
It is also understood mutations of VHL genes are also part of causes of other tumours including breast, colon etc.
VHL is the key to understanding how tumors grow and how potential theories can inhibit angiogenesis.
VHL is a tumor suppressor protein that is localized in the nucleus or cytoplasm, the extent to which being dependent on cell density.
The hypoxia-inducible transcription factors have also been shown to play a crucial role in tumour promotion in other cancers including breast, brain, colon, gastric, lung, skin, ovarian, prostate, renal, pancreatic. Increased levels of growth factors result in angiogenesis.
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, vhl.org) 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:
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.
About VHL
VHL or von Hippel-Lindau disease is a genetic form of cancer. VHL patients battle a series of tumors throughout their lives. The VHL gene controls the major feeding
pipeline of every tumor. Curing VHL is one step closer to curing many other forms of cancer.
In patients with VHL, three types of lesions may be found commonly in the pancreas:
Cysts
Serous microcystic adenomas, or “cystadenomas”
Islet cell tumors, or pancreatic neuroendocrine tumors (pNETs)
These lesions are very different from the common pancreatic tumors and cysts that may be detected among patients in the general population that are not diagnosed with VHL.
Pancreatic cysts may be found in a large number of people with VHL, with wide variation among families. About 75% of people with VHL develop pancreatic cysts. Many cysts, even very large ones, may be present without causing symptoms, in which case no treatment is required. In some cases, enlarged cysts may press against surrounding organs, such as the stomach, and cause discomfort. Surgical or endoscopic drainage of a large cyst may provide relief.
Pancreatic tumors are found in up to 17% of people with VHL. Serous microcystic adenomas are the most common. They are benign and appear as honeycombed clusters of small cysts that look solid on the scans. These generally do not need to be removed, unless they are causing obstructions to the normal flow of fluids and enzymes that cannot be managed otherwise.
VHL-related pancreatic lesions are generally considered to be one of the least symptomatic among the lesions associated with VHL. Depending on their size, type, and location, cysts and tumors of the pancreas can cause functional problems, as well as structural problems. The medical team may request additional tests to detect abnormal hormonal function. Cysts and tumors may block one or more of the ducts that carry essential fluids from the pancreas to the digestive tract, causing jaundice, pain, inflammation, infection, diarrhea, constipation, fatty stools, weight loss, and other digestive complaints. Blockage of the delivery of insulin may cause digestive problems, or diabetes. Fortunately, there are replacements that can be taken by pill or injection. Insulin or digestive enzymes may need to be prescribed to maintain health. Figuring how much of which enzyme is needed at what times is not an easy thing to calculate. A gastroenterologist, or naturopath, familiar with pancreatic insufficiency and digestive imbalance can assist in achieving the right balance to improve quality of life.
Pancreatic Neuroendocrine Tumors (pNETs)
Although rare, the most serious pancreatic issue is solid tumors, not cysts, arising within the islet cells of the pancreas. In VHL, these are most commonly pancreatic neuroendocrine tumors (pNETs). Most of these tumors do not metastasize. Although the minority, pNET that do metastasize typically spread to the liver, bone, or other organs. Hence, careful evaluation of pNETs, while they are localized, is necessary to allow timely resection. PNETs are almost never functional in VHL, meaning they do not release hormones that cause symptoms, so chemical blood or urine tests will not help to determine their nature. MRI using gadolinium as the contrast dye is the preferred routine surveillance method for the abdomen, unless MRI is contraindicated, in which case contrast-enhanced CT may be used.
Researchers have identified two variables that may be considered when deciding whether intervention is required: tumor size and genetics.
Size:
Size is the main criteria for determining approximate risk level for pNETs. Tumors that are greater than, or equal to, 3 cm should be considered high risk and be evaluated for surgery. pNETs with a diameter between 1.2-1.5 cm and 3 cm should be considered moderate risk and be monitored closely. Those smaller than 1.2-1.5 cm are considered low risk. The location of the tumor within the pancreas should also be taken into consideration, as tumors in the head of the pancreas are typically removed when they are smaller to allow for less extensive surgeries.
Genetics: The VHL gene has three distinct parts, called exons. Two large studies have shown a higher rate of dangerous pNETs (those that may metastasize) among people who have an alteration in exon 3 of the VHL The genetics of a patient may be used to better determine risk level in those patients who fall into the “moderate risk” category based on size (diameter between 1.2-1.5 cm and 3 cm).
It is important to note that the decision on when and how to intervene on a pNET is complex and requires a multidisciplinary team discussion that includes a VHL pNET specialist.
Possible Effects on Pancreatic Function
While cysts are benign, they may block one or more of the tiny tubules in the pancreas that deliver pancreatic enzymes to the gut. It is somewhat like stepping on a garden hose. Even though the pancreas is still making these enzymes, they are unable to get to where they need to go to aid digestion. In late stages, when the pancreas is widely replaced by cysts, the number of cells in the pancreatic islets may be low, leading to insufficient secretion of hormones and increase in blood sugar levels.
Tumors and/or cysts near the common bile duct can also block the gallbladder from delivering bile. Blockages near the liver can affect liver function. Be sure to discuss any pain or yellowing of skin or eyes with a doctor. These symptoms of jaundice may indicate a problem with liver function.
Diabetes is the condition that occurs when the pancreas does not make enough insulin to keep blood sugar within the normal range. Diabetes occurs rarely in non-operated patients. The risk increases in patients with repeated pancreatic tumor resections and especially among those with severe pancreatic cystic disease. This can be treated with pills that can help the pancreas make more insulin, pills that tell the liver to make less sugar, or injections of insulin to replace what is not being produced or delivered. An endocrinologist and a certified diabetes educator (dietitian or nurse) can help with the management of diabetes and help develop a personalized plan for meals and exercise.
Pancreatic insufficiency is when the pancreas is not making the digestive enzymes, or when their delivery to the gut is blocked. Removal of all or part of the pancreas reduces the ability of the pancreas to make and deliver these enzymes. When the food is not broken down, the nutrients cannot be delivered to the cells. The food simply goes right through and out the other end without being digested and absorbed. In other words, the cells are still starving. This condition is called malabsorption. One major sign of malabsorption is weight loss. It is critically important to your health to get your digestion back in balance. This is more than an annoyance; it is one of the keys to your health.
Symptoms of malabsorption include diarrhea, bloating, cramping, abdominal pain, fatty stools (appear frothy and oily on the top of the toilet bowl water, with a strong odor), and possible deficiencies of fat-soluble vitamins (A, D, K, and E). A registered dietitian who works with clients with cystic fibrosis, pancreatic cancer, or pancreatic insufficiency should be able to help with this problem.
I am getting abdominal pain
Liquid diarrhea
Sudden blurry vision which scares me because I think I have gone blind with both eyes
Tiredness
Fizzy burps
Odorous fatty stools
Pancreatic cancer is one of the most lethal malignancies in the world, with mortality rates being close to the incidence rates. The incidence rates of pancreatic cancer is 3%. Most patients with pancreatic cancer are diagnosed at the advanced stage due to the deficiency of a standard program for screening patients at a high risk of pancreatic cancer,leading to a poor prognosis with a 5-year survival rate of <7%. Therefore, it is very important to clarify the mechanisms of pancreatic cancer progression and develop novel therapeutic strategies to improve the overall survival of affected patients.
Previous studies have demonstrated that mircoRNAs (miRNAs/miRs) are implicated in the development of pancreatic cancer as both oncogenes or tumor suppressors. miRNAs regulate gene expression at the post-transcriptional level by binding to the complementary 3′-untranslated regions (3′-UTR) of target genes.Studies have shown that miRNAs are involved in many biological processes, such as proliferation, migration and invasion, by regulating the expression of their target genes. Increasing evidence shows that miR-21 is markedly overexpressed in numerous types of cancer, including pancreatic cancer.It has been reported that miR-21 acts as an oncogene participating in the development of pancreatic cancers and may be utilized as a diagnostic or prognostic miRNA for pancreatic cancer. In pancreatic cancer, miR-21 decreased the expression of Slug and Fas ligand, and influenced the growth, apoptosis and invasion of pancreatic cancer cells. Another study indicated that miR-21 regulated the epithelial growth factor receptor/AKT signaling pathway through targeting Von Hippel-Lindau tumor suppressor (VHL) in glioblastomas; however, the function of the interaction of miR-21 and VHL in pancreatic cancer has remained elusive.
VHL is a component of the protein complex that includes elongin B, elongin C and cullin-2, and possesses ubiquitin ligase E3 activity. When oxygen supply is adequate, hypoxia-inducible factor (HIF)-1α is hydroxylated by prolyl hydroxylase proteins and is then recognized by VHL, leading to the ubiquitination and degradation of HIF-1α. However, numerous types of solid tumor are anoxic; HIF-1α may be upregulated due to inactivation of VHL, thus promoting the progression of tumors. VHL is a tumor suppressor inactivated in various types of tumor through diverse mechanisms, including the regulation by miRNAs. Numerous miRNAs have been reported to regulate the expression of VHL; for instance, miR-101 and miR-155. However, whether miR-21 and VHL contributed together to the development of the pancreatic cancer remained to be clarify. The present study demonstrated that VHL is a direct and functional target of miR-21 and is downregulated in pancreatic cancer cells. Knockdown of miR-21 increased the expression of VHL and modulated the HIF-1α/vascular endothelial growth factor (VEGF) pathway, leading to inhibition of the malignant phenotypes of pancreatic cancer.
Von Hippel-Lindau tumor suppressor (VHL) was downregulated in pancreatic cancer tissues compared with pancreatic non-tumor tissues. VHL was identified as a novel direct target of miR-21, by which it is negatively regulated. In PANC-1 cells, inhibition of miR-21 and upregulation of VHL significantly suppressed cell proliferation, migration and invasion. Knockdown of miR-21 inhibited the hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway, while inhibiting the expression of matrix metallopeptidase (MMP)-2 and MMP-9. Silencing of miR-21 inhibited tumor growth in vivo.
About MK-6482
MK-6482 (formerly PT2977) is an investigational, novel, potent, selective, oral HIF-2α inhibitor that is currently being evaluated in a Phase 3 trial in advanced RCC (, a Phase 2 trial in VHL-associated RCC, and a Phase 1/2 dose-escalation and dose-expansion trial in advanced solid tumors, including advanced RCC . Proteins known as hypoxia-inducible factors, including HIF-2α, can accumulate in patients when VHL, a tumor-suppressor protein, is inactivated. The accumulation of HIF-2α can lead to the formation of both benign and malignant tumors. This inactivation of VHL has been observed in more than 90% of ccRCC tumors. Research into VHL biology that led to the discovery of HIF-2α was awarded the Nobel Prize in Physiology or Medicine in 2019.
Study results indicated that MK-6482 demonstrated durable efficacy in patients with Von Hippel-Lindau disease-associated clear cell renal cell carcinoma, pancreatic lesions, and hemangioblastomas by targeting the underlying pathophysiology of the disease.
Patients with Von Hippel-Lindau disease (VHL) are at risk for several cancers, including clear cell renal cell carcinoma (ccRCC). Inactivation of VHL results in constitutive activation of the HIF-2α transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, has shown favorable safety and antitumor activity in a phase 1/2 study.
A study to evaluate the efficacy and safety of Belzutifan monotherap in participants with advanced pheochromocytoma/paraganglioma (PPGL) or pancreatic neuroendocrine tumor (pNET). The primary objective of the study is to evaluate the objective response rate (ORR) of belzutifan per Response Evaluation Criteria in Solid Tumors Version
Findings presented at the 21st Annual Meeting of the Society of Urologic Oncology (SUO) indicated that MK-6482 demonstrated durable efficacy in patients with Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), pancreatic lesions, and hemangioblastomas by targeting the underlying pathophysiology of the disease.
MK-6482 demonstrated durable efficacy in patients with Von Hippel-Lindau disease-associated clear cell renal cell carcinoma, pancreatic lesions, and hemangioblastomas by targeting the underlying pathophysiology of the disease.
The VHL mutation causes cells to lose their ability to respond to oxygen levels properly, and leads to a buildup of HIF proteins inside the tumor cell. This process incorrectly signals that the cells are starved of oxygen, causing the formation of blood vessels and driving tumor growth. The inactivation of the VHL tumor-suppressor protein also is observed in more than 90% of sporadic RCC tumors. MK-6482 directly targets HIF-2a, hindering cancer cell growth, spread and abnormal blood vessel development.
This drug is used for reducing pancreatic tumours too.
Non-RCC tumors also derived benefit from MK-6482 in the study. A baseline MRI from 1 patient in the study showed shrinkage in a left cerebellar hemangioblastoma at week 24 compared with baseline. In another patient with a spinal hemangioblastoma, a decrease in tumor size from baseline to the 24-week mark was also observed.
The non-RCC disease sites evaluated in the study included central nervous system hemangioblastoma (80.3%), pancreatic lesions (50.8%), retinal lesions (27.9%), epididymal cystadenomas (16.4%), adrenal lesions (4.9%), endolymphatic sac tumors (1.6%), and 3.3% of patients had other disease sites.
Transcription:
We put on 61 patients on the study across multiple centers in both the US and in Europe. The primary end point of the study, as I said, was evaluating the overall response rate in patients with renal tumors. And the renal overall response rate for the study was 36%, which is quite impressive. What adds even more interest here is that, in addition, another 11% or so of the patients had achieved a partial response. But by RESIST criteria, we need to make sure that those partial responses persist at least over an 8-week period. So, they need to be confirmed after the first time we identify somebody as a partial responder and in this 11% of the patients, that has not occurred, and it's possible that we will see those patients responding as well. Or having confirmed response as well, so time will tell.
It's also possible that some other patients who will now have tumor regression not making the 30% cut off that we need for RESIST classification as a partial responder may continue to have tumor shrinkage, and this is something we've seen this with this drug, you can get ongoing tumor regression. So, it's possible that some of those that have not made the cut off for partial response eventually do. In fact, if you look to see how many patients on the study had some degree of tumor regression, the answer is that the vast majority had well over 90%. So almost everybody who went on the study had some degree of tumor regression. It was more pronounced in some and less in some. And so really time will tell what the eventual confirmed response to a person with this drug. But what we have already is, I think, quite encouraging.
We also looked to see whether you could see tumor shrinkage in other organ systems as a set. And, you know, when we look at pancreatic neuroendocrine tumors, which, you know, malignant tumors that occur in the kidney, I’m sorry, in the pancreas, that are also managed surgically, for the most part, when they reach a certain size threshold, we saw that those were shrinking as well. In fact, we saw an overall response rate of around 80% with those tumors. Now the number of patients with those tumors was less than the number of tumors with kidney cancer because we didn't require that all patients who entered the study have a pancreatic tumor. …there was a sizable number of patients with pancreatic neuroendocrine tumors and we've seen some very, very convincing responses in these tumors. I'd mentioned that with the… targeted agents, we don't really see that much effect on CNS… And that's different with this drug. We are seeing tumor regression in the central nervous system. And when you look at brain… approximately 30% of the patients had lesions, and we used slightly different criteria for evaluating these patients than we do for the kidney and pancreas because of... But with the criteria we used, we did see approximately 30% of the patients have an appreciable tumor response that we were able to classify as partial responses.
Last but not the least, significant morbidity in these patients because of lesions in their eye, they also don't have these vascular lesions called angioma… in the retina. And depending on the location, frequency, size, and other factors, they can have a significant impact on the vision of these patients. And again, to date, I have not had encouraging results with any other drug that I have implied in these patients. But, you know, very encouragingly, we see that most patients who had a… to begin with, had either an improvement or stability of their disease. So, we had around 15 patients that we thought were evaluable. From this perspective, 11 of those had an improvement as assessed by both, you know, ophthalmologist centers, but more importantly by a central group of ophthalmologists who looked at all the data. And 4 of the patients who didn't have, you know, notable improvements had stability of disease. So, on the whole, I'm very, very impressed with the activity we see this see with this agent.
The other aspect we were trying to look at with this drug was tolerability. As I mentioned, some of the earlier agents that we looked at, including… were hampered to some extent by the ability of patients to continue taking these drugs for a reasonable period of time. We haven't seen that the vast majority of patients remained on study over the one year… over the 60 to 68 weeks that we've actually followed these patients on the study to date. Most of them have remained on study. Side effects we've seen have been very mild for the most part, most common side effect has been anemia which we would predict will occur, it actually tells us the drug is doing what it's supposed to because HIF-2α is responsible for transcriptional activation of a protein called erythropoietin, which is very important in making red blood cells, so when you interfere with the process, you are going to see a drop in hemoglobin levels. And so, anemia was not clinically significant in everybody. You know, in a small number of patients anemia was sufficient to require intervention. And that intervention usually took the form of either supplementing… which we can do or, you know, in rare cases, transfusion, or in some cases, a reduction in the dose of the drug to see if they were going to come back. The vast majority of patients again, it has not been a clinical problem. And those in whom it’s been an issue, we've been able to manage the anemia fairly well.
So, on the whole, you know, I'm very encouraged with activity. And I'm also encouraged by the fact that we have a tolerability adverse event profile that's at least to date much better than what I've seen with other agents. Longer follow up is obviously needed. But what we have today, I think is, you know, sufficiently encouraging for me to feel very optimistic about the goal of such strategies in patients with VHL.
The FDA has granted a Breakthrough Therapy designation to MK-6482, a novel HIF-2a inhibitor, as treatment of patients with von Hippel-Lindau disease-associated renal cell carcinoma who have non-metastatic tumors that measure less than 3 centimeters in size, unless immediate surgery is needed. The FDA has also granted an Orphan Drug designation to MK-6482 for the treatment of VHL disease alone.
Ref
- https://www.cancernetwork.com/view/ramaprasad-srinivasan-md-phd-on-the-results-of-mk-6482-in-vhl-associated-disease
- https://www.merck.com/news/fda-grants-breakthrough-therapy-designation-to-mercks-novel-hif-2%CE%B1-inhibitor-mk-6482-for-treatment-of-certain-patients-with-von-hippel-lindau-disease-associated-renal-cell-carcinoma/
- The FDA’s Breakthrough Therapy designation is granted to expedite the development and review of medicines that are intended to treat serious or life-threatening conditions and that have demonstrated preliminary clinical evidence indicating that the medicine may provide a substantial improvement over available therapy on at least one clinically significant endpoint. The FDA’s orphan drug designation is granted to medicines that are intended for the treatment, prevention or diagnosis of rare diseases that affect fewer than 200,000 people in the U.S.
- https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.5003
- https://www.clinicaltrials.gov/ct2/show/NCT04924075
- https://www.vhl.org/patients/what-is-vhl/types-and-manifestations/pancreatic-cyststumorscancer/
- https://cancerletter.com/the-cancer-letter/20191213_4/
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