The discovery of angiogenesis inhibitors: A new class of drugs: Transcript: Part 4
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So I decided that little or no progress would be made in translating angiogenesis research from laboratory to clinic unless we ourselves demonstrated proof of principle in the clinic. Throughout the last century and up to 1990, all children's hospitals experienced the problem of infants with life-threatening or sight-threatening hemangiomas. Hemangiomas represent a form of pure, but abnormally excessive capillary blood vessel growth.
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44. Small facial hemangioma
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Hemangiomas occur in 1 out of 100 newborn babies and in approximately 1 out of 4 premature babies. They continue to grow after birth, and reach peak growth at about 4 months and then by 1 year, slow their growth. They begin to regress by 1-2 years and have usually disappeared spontaneously by 3-5 years or more.
Small hemangiomas as shown in this slide--on the side of this boy's face--usually require no treatment. |
45. Pre-hemangioma
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However, about 3-5% of hemangiomas are life-threatening, if they arise in the brain, heart, airway, or liver. Up until 1990 the large hemangiomas in the liver caused a mortality of approximately 50%. Hemangiomas may also threaten sight by damaging an eye. Conventional therapy for these hemangiomas has been administration of corticosteroids (in the form of prednisone) to accelerate regression (or involution) of the hemangioma. Corticosteroids dramatically regress hemangiomas in about 30% of patients, but have little effect in 35%, and fail completely in the other 35%. |
46. Hemangioma with eye involvement
47. Large hemangioma
48. Regression of large hemangioma
49. Key steps demonstrating Interferon-alpha is an angiogenesis inhibitor 1980-89
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These next slides show an example of a baby in 1982 whose facial hemangioma failed to respond to corticosteroids. Because there was no other therapy at that time, the hemangioma continued to grow until it closed the left eye by 6 months, became huge by 1 year, and by the time it had regressed spontaneously (10 years), she was blind in the left eye.
Then, in 1998, I received a call from Dr. Carl White of Denver who was caring for a child with hemangiomas in the lung. All corticosteroid therapy had failed. These children usually die of hemoptysis (coughing up blood) and heart failure. Dr. White had heard a seminar about the antiangiogenic (activity of interferon alpha in animals. Because hemangiomas in the lung were almost universally fatal at that time, and because interferon alpha was already an approved drug for hepatitis and other anti-viral uses, and was used for cancer, we discussed over the phone the use of 3 million units per meter square each day as a low dose that would not cause the side effects of the 10-20 million units of interferon used for cancer or hepatitis. Dr. White received approval, and the hemangioma regressed over the ensuing year. The patient remained on low dose interferon alpha therapy for 6 more years and has now been off the drug 5 years. This first patient to receive anti-angiogenic therapy was reported in the May 4, 1989 issue of the New England Journal of Medicine |
50. Key steps demonstrating Interferon-alpha is an angiogenesis inhibitor 1992-95
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Drs. Alan Ezekowitz, John Mulliken, and I then obtained permission from the Committee on Clinical Investigation at Children's Hospital and from the FDA to treat life-threatening or sight-threatening hemangiomas that had failed all conventional therapy, with low dose daily interferon alpha. |
51. Infant with hemangioma of back
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This slide shows one of our first patients in 1990. This huge hemangioma on her back is trapping platelets, so that she is bleeding into the hemangioma, and it continued to grow despite high dose steroids. |
52. Infant with hemangioma of back-3 months interferon-alpha treatment
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In this slide the child has been on interferon alpha for approximately 3 months, and the growth has slowed. |
53. Infant with regression of hemangioma of back-11 months of treatment
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In this slide at 11 months of age, still on interferon-alpha, the hemangioma has completely disappeared--accelerated regression, but it took a long time. We learned that these children require a daily injection of interferon alpha at home, not unlike chronic administration of insulin. |
55. Child at 7.5 years
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This slide shows her at 7.5 years of age (off interferon alpha therapy 6.5 years). No recurrence. |
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This slide summarizes our 10-year experience. Eighty-three life-threatening hemangiomas were treated from 1990 to 2000. Seventy-two complete regressions (in other words, 87% complete response). No recurrences in this group. Eleven hemangiomas failed to regress with any therapy, including interferon alpha.
There were 6 deaths, (5 of which were Kaposi hemangioendothelioma [KHE]). There have been no deaths in the past 3 years. The mortality from liver hemangioma, which was up to 40% prior to 1990, is now down to approximately 3%. Approximately 4% of children on interferon alpha have neurotoxicity in the form of delayed walking or spasticity of the lower limbs.
We had reported that hemangiomas overexpressed bFGF and also VEGF (although for shorter intervals). We found that bFGF levels were elevated in the blood and urine of patients with growing hemangiomas. bFGF levels fell toward normal when the hemangiomas underwent regression. Josh Fidler reported that interferon alpha inhibited overexpression of bFGF. In a collaboration with him, we recently demonstrated that in growing hemangiomas in the skin, normal expression of interferon beta was decreased while bFGF expression was abnormally increased. During regression of the hemangioma, interferon beta expression increased to normal levels and bFGF levels decreased toward normal.
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57. Low grade giant cell tumor of jaw
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By the mid-1990s we began to ask if there were any cancers that produced bFGF as their only or main angiogenic mediator. |
60. Giant cell tumor-6 months on interferon-alpha 2A
61. Giant cell tumor-off treatment for 3 years
62. X-ray; off treatment for 1 year
63. X-ray; off treatment for 4 years; bone regrowth
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The next few slides show a young girl referred from the Massachusetts General Hospital whose baseball-sized tumor (low grade giant cell tumor) in the left jaw was removed by surgery, but recurred within 3 months. Then the left jaw was removed (radical mandibulectomy), but the tumor recurred a second time. Radiotherapy was advised, but because this prevents growth of the face on one side, and can lead to severe deformity, we obtained a urine bFGF, which was abnormally elevated. Therefore, we obtained permission to treat with the same regimen of interferon-alpha as for life-threatening hemangiomas. The tumor regressed completely over approximately 1 year of therapy, after which interferon alpha was discontinued and the tumor has not recurred. The surprise was that the bone in the left jaw grew back completely, and as you can see from the slides, last year she had successful tooth transplants. There are now 8 similar successful cases at the Massachusetts General Hospital, and at other hospitals. |
66. Infant with angioblastoma of hand
67. Angioblastoma of hand without therapy
69. Angioblastoma of hand-complete regression; interferon 11 months
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Here is another example of using daily low dose interferon-alpha therapy (3 million units/meter /day) to treat a tumor that is refractory to conventional therapy and is producing bFGF. It is an angioblastoma in the hand and wrist of an infant. The tumor board recommended amputation of the hand. The fifth metacarpal of the right hand has been completely eroded. After interferon alpha therapy was initiated there was complete regression of the lesion by 11 months. The bone healed completely. He has been off interferon alpha for 1 year 8 months. |
70. MRI-pelvic tumor
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Here is a magnetic resonance image of a 17-year-old girl who had a very large tumor of the pelvis, which had eroded the sacrum causing pain and loss of urinary control. She used an indwelling urinary catheter. The tumor was inoperable and continued to grow despite a full course of radiotherapy. She was sent home for terminal care. Her urine bFGF was abnormally elevated. Interferon alpha-2a was started at 2 million units and later 3 million units/day total dose, subcutaneously. |
71. MRI-Pelvic tumor 80% regression
72. MRI-Pelvic tumor 90% regression
73. Patient post-treatment
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She had an 80% regression in 10 months and a 90% regression in 1 year 7 months and now she is off interferon alpha. Her sacrum has healed and she has urinary control without a catheter. Now, there are several reports in the literature where low dose interferon alpha is being used as anti-angiogenic therapy for selected patients with refractory cancer. For example, a 20-year-old female with hemangioendothelioma, metastatic to brain and bones, was successfully treated with interferon alpha with complete regression of all tumors (see Oncology Reports 7:145, 2000). |
75. Endostatin
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If we now look at the more potent angiogenesis inhibitors, endostatin is an example. It was discovered by Michael O'Reilly in our lab when he was a post-doctoral fellow. It is a 20 kilodalton internal fragment of collagen XVIII, a basement protein, found in many tissues, but especially in the vascular wall. |
76. Endostatin Phase I Clinical Trial Oct 99-Nov 00
77. Patient with metastatic pancreatic cancer before treatment
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It is currently in Phase I/II clinical trials in Boston, Houston, and Madison. What is striking is the virtual lack of side effects. As an example, here is a patient who has been on endostatin almost a year and she allowed her picture to be shown because she is doing very well. She had an islet cell cancer of the pancreas metastatic to the liver, which failed all chemotherapy and continued to grow. Her chemotherapy was discontinued a year ago (last June 2000), because of cardiotoxicity and because it was felt that she was terminally ill and that there were few other options. |
78. Pancreatic cancer; metastases regressing on Endostatin 8 months
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However, she had been on the waiting list for endostatin and began daily intravenous endostatin therapy in August last year. Her tumor gradually stabilized, and by December 2000 she was started on continuous endostatin therapy, administered from a small wearable pump. Since then her periodic scans reveal continuing, measurable tumor regression. Her hair has grown back, she is back to normal weight and stamina, and she has had no side effects or toxicity. |
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So to summarize, there are about 20 angiogenesis inhibitors in clinical trials throughout the United States in more than 100 medical centers. Seven angiogenesis inhibitors are in Phase III. Of interest is that similar angiogenesis inhibitors are in clinical trial for the treatment of eye diseases dominated by local angiogenesis. Of 5 such inhibitors, 3 are currently in Phase III.
So, what is the take-home message? Angiogenesis-dependence seems to provide a unifying principle for diseases which have different names and are handled by different specialists, but are mediated by the same angiogenic molecules, and can be treated by the same angiogenesis inhibitors.
Thus, the ophthalmologist trying to stop angiogenesis in the eye is treating a similar process as the rheumatologist who is trying to prevent new vessels from destroying the joint cartilage, as the gynecologist who is trying to arrest angiogenesis in endometriosis. As each specialty group discovers that certain of the diseases that they treat are angiogenesis-dependent, many new papers on angiogenesis research appear in their specialty journals.
Eventually angiogenesis inhibitors may be used in combination with chemotherapy and with radiotherapy and with immunotherapy, or with each other. Clinical trials are already underway with some of these combinations. Hopefully, this approach will one day reduce drug resistance and reduce the side effects of chemotherapy. It may someday be possible to convert cancer to a chronic manageable disease like what has happened in the treatment of myocardial infarction.
There are two caveats. One is, never listen to a physician who shows you single cases&unless they are the first case. There was a first case of insulin; there was a first case of penicillin. I have shown you only first cases. And finally, speakers are advised not to end with a take home message that is too simple because it simplifies the great lecture you have given. However, I will make an exception. If you came in late, the take-home message for this lecture is&if you should happen to drain the Pacific Ocean you should not be surprised that the islands are connected!
Thank you very much for the honor of this lecture. |
