PARP Inhibitors for Uterine Cancers

gdpawel

Some cell-based assay labs have explored the biology of PARP inhibitors, alone and in combination, in actual human tumor primary culture microspeheroids (microclusters), in breast, ovarian and other cancers. In these investigations, the lab applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations. As seen with PARP inhibitors, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

The Sunday, April 3, 2011, experimental and molecular therapeutics poster session at the American Association for Cancer Research (AACR) 102nd annual meeting included Dr. Robert Nagourney's Rational Therapeutics presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors he explored the activities, synergies and possible clinical utilities of these novel compounds.

The results of functional analysis with the mTOR/P13K and MEK/ERK inhibitors, BEZ235 and AZD6244, alone and in combination in human tumor primary culture microspheroids (microclusters): Exploration of horizontal pathway targeting. While the profiles of each drug alone are of interest, the profiles of the drugs in combination are better still.

The phenomenon of cross-talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When clinical therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies. This is what has been observed with these duel inhibitor combinations. What is interesting is the fact that the activities cut across tumor types. Melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths. Once again, we find that cancer biology is non-linear.

Moreover, cancers share pathways across tumor types, pathways that might not intuitively seem related. This is the beauty of cell-based functional profiling platform. It allows the exploration of drugs and combinations that most oncologists wouldn’t think of. It is these counterintuitive explorations that will likely lead to meaningful advances.

The findings were instructive. First, it saw a good signal for both compounds utilizing the Ex-vivo Analysis of Programmed Cell Death (EVA-PCD) platform (functional profiling). Second, it saw disease-specific activity for both compounds. For PI3K inhibitors, the highest activity was observed in uterine cancers.

This has interest, because uterine carcinomas are often associated with a mutation in the PTEN gene. PTEN is a phosphatase tumor suppressor that functions to block activation of the PI3K pathway. Thus, mutations in the tumor suppressor unleash PI3K signaling, driving tumors to grow and metastasize. Blocking PI3K provided a strong signal, indicating that this approach may be very active in tumors associated with these oncogenic events.

Functional profiling measures biological signals rather than DNA indicators, which plays an important role in cancer drug selection and is demonstrably greater and more compelling data currently generated from DNA analyses. The results of their investigation support the clinical relevance of targeting the MEK/ERK and PI3K/mTOR pathways and more importantly, suggest "dual" pathway inhibition (horizontal) to be a productive strategy for further clinical development. Disease specific profiles and sequence dependence are explored and reported.

PARP is a very active enzyme involved in the repair of single-strand breaks in DNA or modified bases. It binds to DNA damage and adds multiple sugar molecules to the DNA that act as a beacon to recruit other components of DNA repair.

Emerging work on assays (PARP levels correlating with response to PARP inhibitors) have shown pretty good response with PARP inhibitors as single agents and some results combining the PARP inhbitors with mustard alkylators, platins and drug combinations to optimize PARP inhibitor combinations. These results, though exploratory, suggest a superior approach for drug development, allowing the lab to identify important leads much faster than the clinical trial process.

Source: Robert A. Nagourney, Paula Bernard, Federico Francisco, Ryan Wexler, Steve Evans, Rational Therapeutics, Long Beach, CA. Proceedings of AACR - Volume 52 - April 2011.

American Association of Cancer Research (AACR) Meeting 2011

http://robertanagourney.wordpress.com/2011/04/28/poster-from-rational-therapeutics-session-at-2011-aacr-meeting/

Songflower

Parp Inhibitors
It sounds very interesting and gives some hope. Problem is they are not available to the majority of us. May I ask what your career is? Are you in medical research? We appreciate the information.

Diane

gdpawel

Songflower said:

Parp Inhibitors
It sounds very interesting and gives some hope. Problem is they are not available to the majority of us. May I ask what your career is? Are you in medical research? We appreciate the information.

Diane

Parp Inhibitors
Diane

My motivation is the satisfacton of knowing that I've helped to increase the knowledge of informed consent. My bailiwick has been my dearly beloved wife's experience as a cancer patient and my research over the last ten years on cell function analysis, which has no boundaries across cancer types.

Greg

Songflower

gdpawel said:

Parp Inhibitors
Diane

My motivation is the satisfacton of knowing that I've helped to increase the knowledge of informed consent. My bailiwick has been my dearly beloved wife's experience as a cancer patient and my research over the last ten years on cell function analysis, which has no boundaries across cancer types.

Greg

Thank you Greg
Thank you Greg. Your research over 10 years certainly shows. Thank you for helping us; I read one article on Parp inhibitors but it was sketchy. Those of us with agressive cancers are often sick and it's hard to research at the same time. Once again, thank you for thinking of us and helping us.

Diane

gdpawel

Songflower said:

Thank you Greg
Thank you Greg. Your research over 10 years certainly shows. Thank you for helping us; I read one article on Parp inhibitors but it was sketchy. Those of us with agressive cancers are often sick and it's hard to research at the same time. Once again, thank you for thinking of us and helping us.

Diane

Diane
You mention "aggressive" cancers. Do you have one of the syndrome ovarian cancers, BRAC1, BRAC2 or Lynch Syndrome? It makes one much more likely to develop certain types of cancer, however, it may render one more hypersensitive to chemotherapeutics. BRAC genes may provide therapeutic opportunities with PARP inhibitors. Melphalan may also provide therapeutic treatment for BRCA-related ovarian cacrinoma. BRCA mutations are associated with an improved outcome and enhanced sensitivity to platinum chemotherapy, yet recurrence and platinum resistance remain a major problem and highly effective regimens following platinum failure do not yet exist. Melphalan is a bifunctional alkylator that creates inter- and intra-strand DNA cross-links. In a pharmaceutical screen, a recent study found that Melphalan was shown to be selectively toxic to BRCA2-deficient breast cancer cell lines and produced a longer relapse-free survival in mice than did cisplatin or olaparib (one of the PARP inhibitors). There is increasing evidence to consider BRCA mutation status when selecting chemotherapy regimens, and Melphalan treatment for BRCA-related ovarian cancer merits further investigation.

This has pith my curiosity because my wife was treated with the other alkylating agent Leukeran. She was treated for her original stage IV ovarian primay in 1972 with total abdominal hysterectomy and Chlorambucil (Leukeran), a well tolerated oral drug. By giving chemotherapy more often, at lower doses, it can prevent the regrowth of blood vessels that feed tumors (angiogenesis). Depression of the immune system is slow and reversible, allowing it to regenerate and contribute to recovery. A malfunctioning immune system can fail to stop the growth of cancer cells. She went 24 years before having a recurrence. Although the BRCA1 and BRCA 2 genes where discovered in 1994 and 1995, we did not test for it when she had her recurrence in 1996. However, it was very likely she had Lynch Syndrome. She had a family history of colon cancer and her first bout with cancer was when she was 40 years of age. Although Lynch Syndrome is more commonly associated with endometrial cancer, she developed ovarian. As I mention above, even though a syndrome-type cancer may make one more susceptible to developing certain cancers, it may render one more hypersensitive to chemotherapeutics. A curse and blessing at the same time.

Greg

Songflower

gdpawel said:

Diane
You mention "aggressive" cancers. Do you have one of the syndrome ovarian cancers, BRAC1, BRAC2 or Lynch Syndrome? It makes one much more likely to develop certain types of cancer, however, it may render one more hypersensitive to chemotherapeutics. BRAC genes may provide therapeutic opportunities with PARP inhibitors. Melphalan may also provide therapeutic treatment for BRCA-related ovarian cacrinoma. BRCA mutations are associated with an improved outcome and enhanced sensitivity to platinum chemotherapy, yet recurrence and platinum resistance remain a major problem and highly effective regimens following platinum failure do not yet exist. Melphalan is a bifunctional alkylator that creates inter- and intra-strand DNA cross-links. In a pharmaceutical screen, a recent study found that Melphalan was shown to be selectively toxic to BRCA2-deficient breast cancer cell lines and produced a longer relapse-free survival in mice than did cisplatin or olaparib (one of the PARP inhibitors). There is increasing evidence to consider BRCA mutation status when selecting chemotherapy regimens, and Melphalan treatment for BRCA-related ovarian cancer merits further investigation.

This has pith my curiosity because my wife was treated with the other alkylating agent Leukeran. She was treated for her original stage IV ovarian primay in 1972 with total abdominal hysterectomy and Chlorambucil (Leukeran), a well tolerated oral drug. By giving chemotherapy more often, at lower doses, it can prevent the regrowth of blood vessels that feed tumors (angiogenesis). Depression of the immune system is slow and reversible, allowing it to regenerate and contribute to recovery. A malfunctioning immune system can fail to stop the growth of cancer cells. She went 24 years before having a recurrence. Although the BRCA1 and BRCA 2 genes where discovered in 1994 and 1995, we did not test for it when she had her recurrence in 1996. However, it was very likely she had Lynch Syndrome. She had a family history of colon cancer and her first bout with cancer was when she was 40 years of age. Although Lynch Syndrome is more commonly associated with endometrial cancer, she developed ovarian. As I mention above, even though a syndrome-type cancer may make one more susceptible to developing certain cancers, it may render one more hypersensitive to chemotherapeutics. A curse and blessing at the same time.

Greg

ongoing
I have test negative for Brac 1 and 2. I don't have lynch syndrome. I have UPSC which is uterine papillary serous cancer. It is 5% of uterine cancers. I had breast cancer 11 years ago and took adriamycin/cytoxan and taxotere. I took tamoxifen orally for 5 years and this caused uterine cancer. Chemotherapy is cumulative. I had carbo/taxol for uterine cancer and complete hyst. Relapsed about 7 months later and was responsive to doxil and avastin and also then had hipec. I have painful neuropathy but have it very well controlled with medication. I think lyrica is a miracle drug for nerve pain!

I have never heard of melphalan but it sounds like your wife did very well with it. Those of us on this blog appreciate your research and information.

Thank you!
Diane

gdpawel

Songflower said:

ongoing
I have test negative for Brac 1 and 2. I don't have lynch syndrome. I have UPSC which is uterine papillary serous cancer. It is 5% of uterine cancers. I had breast cancer 11 years ago and took adriamycin/cytoxan and taxotere. I took tamoxifen orally for 5 years and this caused uterine cancer. Chemotherapy is cumulative. I had carbo/taxol for uterine cancer and complete hyst. Relapsed about 7 months later and was responsive to doxil and avastin and also then had hipec. I have painful neuropathy but have it very well controlled with medication. I think lyrica is a miracle drug for nerve pain!

I have never heard of melphalan but it sounds like your wife did very well with it. Those of us on this blog appreciate your research and information.

Thank you!
Diane

Diane
I finally meet one of those people who can develop uterine or endometrial cancer from taking tamoxifen orally for over 5 years. I would mention about this in my postings on the Internet over the years. Told one of my neighbors about it, who was receiving tamoxifen for her breast cancer. And to add insult to injury, what is one of the drugs they can give you for endometrial cancer? Taxmoxifen! You replapsed seven months after receiving Taxol + Carboplatin? Doesn't surprise me. Google: Who needs Taxol? Best of luck to you on your persistent neuropathy. Hope you have a good Physical Medicine and Rehabilitation Specialist on board as one of your "team" of doctors for treatment side effects.

Greg