Hendrick knows pain

Posted by rob on October 29, 2004 under Uncategorized | Be the First to Comment

Hendrick knows pain

By Ed Hinton
STAFF WRITER

October 29, 2004

Regarding Rick Hendrick, the NASCAR team owner who lost his only son, only brother, twin nieces and most of the top management of his racing empire in a plane crash last Sunday, longtime friends have no doubts.

He has turned too much personal tragedy and suffering into too many triumphs, over too many years, for those who know him to question his resilience now.

Hendrick, at 55 a familiar face at the Daytona International Speedway, has been in seclusion since this latest and worst ordeal, but …

“If anybody can stand it, he can,” said H.A. Wheeler, president of Lowe’s Motor Speedway, which lies less than a mile from the massive Hendrick Motorsports compound near Charlotte, N.C.

In 1996-97, Hendrick fought a two-front personal war for survival, against a rare form of leukemia and against federal prosecutors who wanted him sentenced to 210 years in prison — this while doctors couldn’t guarantee he had 210 hours left.

“I never saw him cry about it. I never saw him throw up his hands. There was no `Why me?’ or, `I can’t take this anymore,’” said Max Muhleman, the Charlotte-based marketing executive who 21 years ago got Hendrick his first NASCAR sponsors. They’ve been close ever since.

“Life is a series of tests, and they get harder as we get older,” said John Bickford, stepfather and mentor of Hendrick’s star driver, Jeff Gordon. “Rick Hendrick passes all the tests.”

Legendary driver Bobby Allison for more than a decade has been roundly considered NASCAR’s own version of the biblical figure Job. Allison lost both his racing sons, Clifford in a track accident in 1992 and Davey in a helicopter crash in ‘93. He still suffers debilitating effects of life-threatening injuries that ended his own career in 1988.

“This tragedy over the weekend is, by far, the most monumental thing that any of us [in NASCAR] have ever looked at,” Allison said.

“What we went through was the most horrible thing you can imagine. And we had to do it twice.

“But Rick’s lost 10 people who were members of several families — 10 sets of agonies, all part of the same package.”

Ricky Hendrick, 24, was heir-apparent not only to the most successful team in recent NASCAR history (128 wins and five championships in the elite Nextel Cup series) but the $2 billion a year retail car dealership empire, with more than 60 showrooms nationwide, his father controls.

John Hendrick, 53, stepped in to run both organizations while his brother was fighting the leukemia and the federal rap in the ’90s. Kimberly and Jennifer Hendrick, 22, were John’s daughters.

Jeff Turner was the team’s vice president and general manager. Joe Jackson was a liaison from Gordon’s primary sponsor, DuPont. Scott Lathram, 38, was a helicopter pilot for another team’s driver, Tony Stewart, and a guest of the Hendrick entourage last Sunday.

Richard Tracy, 51, and Elizabeth Morrison, 31, were staff pilots in the Hendrick fleet that includes private jets, but were flying the turboprop Beech King Air that crashed into a Virginia mountainside minutes before the start of the Subway 500 at nearby Martinsville Speedway.

Hendrick is grieving for every one of them as a family member lost, say those who know his mind, his sense of personal responsibility for 460 employees of his racing team and the thousands who work at his dealerships.

“How much can the human psyche deal with in a short period of time?” Wheeler wondered. “If you look at his trial, his leukemia, his father dying [in July, devastating an extraordinary bond] and now this, they’re all in a fairly short period of time, as far as a lifetime is concerned.”

In the holiday season of ‘96, Hendrick was given a diagnosis of chronic myelogenous leukemia, an especially deadly and difficult to treat form of the disease … and then a multi-count federal indictment, the major charge being money laundering in relation to the American Honda bribery scandal, where dealers paid corporate executives kickbacks in exchange for more of the highly demanded cars to sell.

Hendrick’s friends were privately outraged, certain he was a mostly innocent victim of grandstanding politics by prosecutors.

“Those guys have a special appetite for nailing big targets,” Muhleman said. “Rick sounded like a big target. One of the guys at American Honda had asked Rick for some loans to help him with a home mortgage. Rick loaned him money, but stopped when they kept asking for it. He didn’t go to them and say, `How about some money in order for me to get some more cars?’”

Hendrick entered a plea-bargain in order to finish the case and get on with his cancer treatments, and received a sentence of one year in home detention, during which he was forbidden from contact with his racing team.

Hendrick was fully pardoned by President Clinton in 2000, so that ordeal is over. But the leukemia is only in remission, not considered cured.

“It’s the kind of cancer that many, many people don’t beat,” Muhleman said. “It’s still serious. But the longer the remission, the better the chance.”

During the worst of Hendrick’s illness, Muhleman sent a public-relations representative to meet with Hendrick and his lawyers regularly during the legal battle.

“He would come back from those meetings and say, `Man, he looks awful today.’ Or, `He’s in such bad shape he can hardly walk.’

“But at the same time he was suffering, Rick got his marrow program started.”

Hendrick raised more than $4 million, helped expand the national bone marrow transplant match network, and gave it unprecedented publicity through his race team on national television.

“Rick was a prodigy,” Muhleman said. “He was still in his 20s, selling cars down in South Carolina, when City Chevrolet came up for sale here in Charlotte. George Shinn [controversial owner of the NBA Hornets] loaned him the money to buy it.

“That’s the dealership that was featured in the Tom Cruise movie, Days of Thunder,” Muhleman said.

The film was conceived after Hendrick invited friend Cruise to take a drive in one of his race cars.

“That was Rick’s first dealership,” Muhleman said.

Now there are more than 60, nationwide, in the Hendrick Automotive Group. His current Nextel Cup team includes drivers Gordon, Jimmie Johnson (who won the Martinsville race last Sunday before he was told the plane had crashed), Terry Labonte and Brian Vickers.

“Once again, he’s put to the test,” said Bickford, who can predict the outcome. “You look at the situation he had with the government, and out of it came a stronger organization. He delegated responsibilities. He took a negative and turned it into a positive.

“He battled leukemia. Look at all the bone marrow recipients and all the attention that’s been brought, all the money raised, all the great things.

“So constantly, these life tests are given to Rick, and he passes the tests, and out of it come stronger things.”

“I don’t think he’s likely to walk away, although many would,” Muhleman said, “and they would not only walk away, but they would get as far away as possible.”

“I have to believe that in the next couple of years the organization will be stronger, and that the whole world will benefit from things that are learned from this catastrophe,” Bickford said. “Rick will see to it that that happens.”

Ed Hinton can be reached at ehinton@tribune.com.

Copyright © 2004, South Florida Sun-Sentinel

 

http://www.sun-sentinel.com/sports/sfl-hendrick29oct29,0,6024739.story?coll=sfla-sports-headlines

Pic Of The Day

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The moon is engulfed in the Earth’s shadow during a total lunar eclipse over Mexico City

KIT Gene Deletions at the Intron 10-Exon 11 Boundary in GI Stromal Tumors.

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Corless CL, McGreevey L, Town A, Schroeder A, Bainbridge T, Harrell P, Fletcher JA, Heinrich MC
J Mol Diagn. 2004 Nov ; 6(4): 366-70
Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in the KIT gene, and the majority of these mutations affect the juxtamembrane domain of the kinase encoded by exon 11. Screening GISTs for KIT gene mutations is important for translational research studies and for providing prognostic information on the likelihood of tumor response to treatment with the kinase inhibitor imatinib mesylate (Gleevec). In a series of GISTs analyzed in our laboratory by a combination of denaturing HPLC and direct DNA sequencing, we identified 19 cases with KIT exon 11 deletions that included from 1 to 14 bp of intron 10 sequence and resulted in loss of the normal splice acceptor site at the beginning of exon 11. Predicted use of the next potential splice-acceptor site was confirmed by cDNA sequencing in 4 cases. Thus, the resulting mutant isoform, deletion KPMYEVQWK 550-558, was the same in all 19 cases. Only two other examples of deletions across the intron 10-exon 11 boundary have been reported, yet among 722 GISTs analyzed in our laboratories these deletions were not uncommon, accounting for 3.9% of exon 11 mutations and 2.6% of all tumors. Loss of KIT intron 10 sequences may be under-recognized if the forward primer is too close to exon 11, or if cases are examined exclusively at the cDNA level. Laboratories that offer clinical screening for KIT mutations in GI stromal tumors should be aware of this class of mutations.

http://www.hubmed.org/display.cgi?issn=15251578&uids=15507676

A novel mode of gleevec (STI-571, Imatinib) binding is revealed by the structure of spleen tyrosine kinase (Syk).

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Atwell S, Adams JM, Badger J, Buchanan MD, Feil IK, Froning KJ, Gao X, Hendle J, Keegan K, Leon BC, Müller-Dieckmann HJ, Nienaber VL, Noland BW, Post K, Rajashankar KR, Ramos A, Russell M, Burley SK, Buchanan SG
J Biol Chem. 2004 10 26;
Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase required for signaling from immunoreceptors in various hematopoietic cells. Phosphorylation of two tyrosine residues in the activation loop of the Syk kinase catalytic domain is necessary for signaling, a phenomenon typical of tyrosine kinase family members. Syk in vitro enzyme activity, however, does not depend on phosphorylation (activation loop tyrosine to phenylalanine mutants retain catalytic activity). We have determined the X-ray structure of the unphosphorylated form of the kinase catalytic domain of Syk. The enzyme adopts a conformation of the activation loop typically seen only in activated, phosphorylated tyrosine kinases, explaining why Syk does not require phosphorylation for activation. We also demonstrate that Gleevec (STI-571, Imatinib) inhibits the isolated kinase domains of both unphosphorylated Syk and phosphorylated Abl with comparable potency. Gleevec binds Syk in a novel, compact cis conformation that differs dramatically from the binding mode observed with unphosphorylated Abl, the more Gleevec-sensitive form of Abl. This finding suggests the existence of two distinct Gleevec binding modes: an extended, trans conformation characteristic of tight binding to the inactive conformation of a protein kinase and a second compact, cis conformation characteristic of weaker binding to the active conformation, characteristic of activated protein kinases. Finally, the Syk-bound cis conformation of Gleevec bears a striking resemblance to rigid structure of the non-specific, natural product kinase inhibitor Staurosporine.

http://www.hubmed.org/display.cgi?issn=00219258&uids=15507431

JunB Deficiency Leads to a Myeloproliferative Disorder Arising from Hematopoietic Stem Cells.

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Cell. 2004 Oct 29; 119(3): 431-43
Passegué E, Wagner EF, Weissman IL

The AP-1 transcription factor JunB is a transcriptional regulator of myelopoiesis. Inactivation of JunB in postnatal mice results in a myeloproliferative disorder (MPD) resembling early human chronic myelogenous leukemia (CML). Here, we show that JunB regulates the numbers of hematopoietic stem cells (HSC). JunB overexpression decreases the frequency of long-term HSC (LT-HSC), while JunB inactivation specifically expands the numbers of LT-HSC and granulocyte/macrophage progenitors (GMP) resulting in chronic MPD. Further, we demonstrate that junB inactivation must take place in LT-HSC, and not at later stages of myelopoiesis, to induce MPD and that only junB-deficient LT-HSC are capable of transplanting the MPD to recipient mice. These results demonstrate a stem cell-specific role for JunB in normal and leukemic hematopoiesis and provide experimental evidence that leukemic stem cells (LSC) can reside at the LT-HSC stage of development in a mouse model of MPD.

http://www.hubmed.org/display.cgi?issn=00928674&uids=15507213

Personalized Medicine in Cancer: Matching Patients and Drugs

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By Kate Ruder
Posted: October 28, 2004

For the first time in quite a while, physicians who treat cancer are genuinely excited about the possibility that â??personalized medicineâ? may soon become a reality for some lung cancer patients.

It has been a year and a half since the drug Iressa came on the market, which works spectacularly in about ten percent of lung cancers patients and fails to help the rest. No one could figure out why.

Last spring, two groups of researchers figured out that most people who respond to Iressa have similar genetic mutations in their tumors. A later study extended the findings to a related drug, Tarceva, which is awaiting approval by the U.S. Food and Drug Administration.

Now that scientists can explain the drugsâ?? effectiveness in some cases, there is hope that they can better predict who will respond to them in the future and that lessons from Iressa and Tarceva can be applied to other cancers.

Just a few months ago, two research hospital laboratories began offering a test to detect the mutations, which occur in a gene called EGFR. The tests have been used in fewer than 200 patients so far, but scientists speculate they could become widely available in three to six months.

â??The simple fact is itâ??s all about matching the right patient with the right drug,â? says Brian Druker of Oregon Health and Science University in Portland, who was a pioneer in developing another drug, Gleevec.

â??Weâ??re in a transition phase where we donâ??t know all the options,â? says Druker, â??but the era of matching patients and drugs is not far away.â?

One of the problems is that all of the patients donâ??t fit into neat boxes, and perhaps they never will. For example, some people without the mutations also respond to Iressa for reasons that are not known, but scientists are expanding their search for key mutations that could explain this.

â??We are looking for mutations in other genes that could explain why some tumors respond to Iressa in the absence of EGFR mutations, and also looking at how and why tumors may eventually become resistant to Iressa,â? says Daniel Haber of Massachusetts General Hospital in Boston.

Haberâ??s colleague at Mass General Thomas Lynch is doing work on Iressa too. He has a clinical trial that is testing patients for the mutations as a predictor of their response to Iressa as an initial treatment. Iressa isnâ??t usually the first option; itâ??s typically given to lung cancer patients who havenâ??t responded to chemotherapy.

Iressa and Tarceva are part of a relatively new class of drugs known as targeted drugs, which are different from traditional chemotherapy drugs because they are designed to specifically hit cancer cells. Unlike chemotherapy drugs which kill healthy and cancerous cells, targeted drugs are supposed to kill only cancer cells.

The vision for these types of drugs was that they would be â??magic bulletsâ? against cancer, but theyâ??ve had their ups and downs.

Iressa didnâ??t work in most people in clinical trials, but it had marvelous, undeniable benefit for a small percentage of people, and for this reason the U.S. Food and Drug Administration approved it in May 2003.

Itâ??s approved for patients with the most common type of lung cancer, non-small-cell lung cancer, which is also the biggest killer among cancers in the United States with 140,000 new cases each year. AstraZeneca makes Iressa.

It took a year for researchers to begin to unravel the reasons behind Iressaâ??s erratic success.

Two groups of Harvard researchers painstakingly sequenced the EGFR gene, for Epidermal Growth Factor Receptor, in lung tumors from patients who responded to Iressa and those who did not. Most responders had the mutations. Non-responders did not.

Both Haber and Lynch were researchers on the study from Mass General. The other study was done by scientists at Dana-Farber Cancer Institute.

â??The studies generated significant buzz,â? says Daniela Gerhard of the Office of Cancer Genomics at the National Cancer Institute. â??It was very important and encouraging for everyone who was trying to use genomics to develop new targets for cancer treatments.â?

It was a buzz for some patients too. After the studies were published, the scientists received calls from patients trying to find out if their tumors had mutations and whether Iressa would work for them.

The problem was the scientists did not have the time or the facilities to do the sequencing.

Thatâ??s when Harvard Partners stepped in. Harvard Medical School-Partners Healthcare Center for Genetics and Genomics (HPCGG) is a Harvard-affiliated institute with DNA sequencers, and they developed a genetic test that could be done â??at costâ? for doctors at Massachusetts General and Dana-Farber.

The test was up and running in August, and the center now screens up to 50 tumors a month for roughly $850 per sample.

â??The discovery [of the EGFR mutations] was made and in a relatively short time we had turned it around into a clinical test,â? says Randall Mason of HPCGG.

At the same time, scientists at City of Hope National Medical Center in Duarte, California, saw the two Harvard studies and set to work on a genetic test for Iressa. It also had a test ready in August and has done fourteen tests to date, mostly for doctors at City of Hope Hospital. Their turnaround is about two weeks.

â??We were pretty excited by the papers and we thought the data was significant, so we immediately started to develop a test to detect the mutations,â? says Juan-Sebastian Saldivar, co-director of the laboratory at City of Hope.

He says that some of the requests for tests have been patient-driven. For example, two patients asked their doctors at City of Hope for the test because they were concerned about a side effect of Iressa, a sometimes fatal kind of pneumonia called interstitial lung disease.

â??Weâ??re not advocating that someone should be tested before they receive Iressa,â? says Saldivar. â??Itâ??s one tool that can be used in decision-making about treatments, but itâ??s not the absolute deal breaker,â? he says.

These tests raise more questions than answers right now, and theyâ??re not even widely available yet. Who should get the test? How should the information be used?

The other question that remains is why certain groups of patients such as nonsmokers and women are more likely to have the mutations and respond to Iressa and Tarceva. While most lung cancer patients are smokers, a small percent of lung tumors occur in people who have never smokedâ??and they tend to respond to Iressa.

It could take a long time to answer these and other questions about why drugs work for some people and not others. But doing so will be critical if medicine is to reach the goal of matching the right drugs with the right patients.

Paez, J. G. et al. EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science (Published online April 29, 2004).
Lynch, T. J. et al. Specific Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib. The New England Journal of Medicine (Published online April 29, 2004).
Pao, W. et al. EGF receptor gene mutations are common in lung cancers from â??never smokersâ? and are associated with sensitivity of tumors to gefitinib and erlotinib. Published online in Proceedings of the National Academy of Sciences on August 23, 2004.

 

http://www.genomenewsnetwork.org/articles/2004/10/28/matchingpatients.php

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