Treating advanced cancers resistant to Paclitaxel/Topotecan/Temozolomide: Probiotic-based Chemotherapy (PCT) targeting cancer stem cells and immune-inhibitory receptors in advanced ovarian cancers and in other advanced metastatic cancers resistant to Paclitaxel/Topotecan/Temozolomide: A pharmaceutical mixture encompassing Veliparib (ABT-888) and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1, CADM1/2,  p53, and TA-p73/p63, INK4a and others, decreases PP2A expression, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance mediated by Paclitaxel/Topotecan/Temozolomide, and stalls advanced ovarian cancers  progression, and prolongs survival, via up-regulation of its target gene, 7/November/2019, 11.59 pm

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Introduction: What they say

A study from the Department of Gynecologic Oncology and Reproductive Medicine,  University of Texas M.D. Anderson Cancer Center, 1155 Pressler Dr., Houston, TX 77030, USA, and others states that “Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. This research paper was published, in the 28 September 2019 issue of the journal “N Engl J Med. (one of the best journals in Clinical Medicine with an impact factor of 70+), by Profs. Robert L. Coleman, M.D., Michael A. Bookman, M.D., others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, the Director-cum-chief Scientist of GBMD, reports that: Treating advanced cancers resistant to Paclitaxel/Topotecan/TemozolomideProbiotic-based Chemotherapy (PCT) targeting cancer stem cells and immune-inhibitory receptors in advanced ovarian cancers and in other advanced metastatic cancers resistant to Paclitaxel/Topotecan/Temozolomide: A pharmaceutical mixture encompassing Veliparib (ABT-888) and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1, CADM1/2,  p53, and TA-p73/p63, INK4a and others, decreases PP2A expression, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance mediated by Paclitaxel/Topotecan/Temozolomide, and stalls advanced ovarian cancers  progression, and prolongs survival, via up-regulation of its target gene


The Significance of the study to Public health relevance:

First, given that: (i) each year nearly 14 million people–more than 2 38,000 patients are diagnosed with ovarian cancer every year worldwide– are diagnosed with cancer globally, and little more than half of them will die due to lack of curative treatment available at present; (ii) cancer deaths globally are expected to be doubled by 2030;  and (iii) cancer causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (i) a way to prevent an individual from being susceptible to cancer by strengthening his/her own immune system (Cancer immunotherapy); (ii) a cheaper alternative to the existing expensive anticancer drugs; (iii) a side-effect-free natural product-based anticancer drugs that target cancer stem cells; and (iv) a way to effectively treat and prevent metastatic progression and relapse of ovarian cancers.

Second, given that: (1) cancer suppressor p53 is mutated in more than 50% of human cancers of different tissue origin; (2) p53 pathway is altered in about 80% of tumors; (3) our understanding is incomplete in terms of molecular targets and the oncogenic/malignant pathways involved in mutant p53-overexpressing tumors; (4) cancer causes the highest economic loss compared to all the known causes of death worldwide; and (5) cancer causes the considerable economic loss worldwide, there is an urgent need to find a way to effectively treat and stall metastatic progression and relapse of mutant p53-overexpressing human cancers.


From research findings to therapeutic opportunity :

(i) Therapeutic strategy:

This study suggests a therapeutic strategy for stalling the progression of p53-deficient/deleted or mutant-p53 expressing advanced metastatic ovarian cancers. By activating tumor suppressor p53’s unmutated “homologous protein such as TAp73/p63” in p53-deficient or mutant-p53 expressing metastatic cancer cells, one can stall their progression.

(ii) Research findings: This study presented here suggests, for the first time, that a pharmacological formulation encompassing Veliparib (ABT-888), by decreasing the expression of its target gene, it may: (i) decrease the expression of a number of oncogenes and DNA repair proteins; (ii) increase the expression of tumor/metastasis suppressor genes, such as TPM1 (Tropomycin 1), & CADM1/2 (Cell adhesion molecule 1/2); (iii) increase the expression of a number of other tumor suppressor genes, including p53/TA-p73/p63, and their target genes, INK4a, p19ARF and others (Figure 1);(iv) decreases the expression of Protein phosphatase 2A (PP2A) and others; (v)activate tumor/metastasis suppressor network; (vi) inhibit immunosuppressive/immune-inhibitory receptors/ molecules; (vii) inhibit the activity and proliferation of cancer stem cells; (viii) inhibit tumor growth; and (ix) promote survival (Figures 1-4). Further, the efficacy of  Veliparib (ABT-888) can be increased by treating cancer patients with probiotic Lactobacillus rhamnosus  (1.0×103 CFU/ml).

Figure 1. Mechanistic insights into how a pharmacological formulation encompassing Veliparib (ABT-888) and/or Lactobacillus Rhamnosus increases the expression of tumor/metastatic suppressors, such as TPM, CADM1/2, p53, TAp73/p63, INK4a, p19ARF and others, inhibits the expression of immune-inhibitory receptors, increases the expression of PP2A, promotes drug sensitivity to cancer cells that are resistant to the treatment of Paclitaxel/Topotecan/Temozolomide , stops the proliferation of cancer stem cells, and stalls the progression of advanced metastatic cancers.

Figure 2 The fact sheet that reveals the current status of PARP1/2 inhibitor Veliparib (ABT-888).

Figure 3 A pharmacological formulation encompassing  Veliparib (ABT-888) may not only function as a tumor/metastatic suppressors agent in advanced metastatic cancers that are resistant to Paclitaxel/Topotecan/Temozolomide,  but also in mutant-p53 expressing human cancers.

Figure 4. A pharmacological formulation encompassing Veliparib (ABT-888) and Probiotic Lactobacillus rhamnosus may attenuate the progression of advanced  metastatic cancers, including advanced metastatic cancers, through induction of tumor/metastatic suppressors, such as TPM1, CADM1/2, p53, TAp73/p63, INK4a, p19ARF and others, and down regulation of PP2A.

Figure 5. While the PARP1/2 inhibitor Veliparib (ABT-888) had been shown to attenuate the progression of high-grade serous ovarian carcinoma, its mechanism of action remains largely unknown.  This study presented here suggests, for the first time, that Veliparib (ABT-888), by up regulating the expression of  tumor/metastasis suppressors TPM1, and CADM1/2  and others (figs.1-4), and down regulating the expression of PP2A, it may sensitize ovarian cancer cells resistant to chemotherapeutic drugs, and attenuate the progression of advanced metastatic ovarian cancers and other advanced cancers.

 

Thus, a pharmacological formulation encompassing “Veliparib (ABT-888) or its analogs/functional/mechanistic equivalents”, either alone or in combination with other known anti-cancer/metabolic drugs, and/or, probiotics enriched with anti-cancer activity, such as  Lactobacillus rhamnosus,” may be used to inhibit the progression of advanced  cancers, including high-grade serous ovarian carcinoma, and thereby promote disease-free survival (Figure 3-6).

Details of the Research findings:

Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.

Amount: $1, 500#

Undisclosed mechanistic information: How does Veliparib (ABT-888)increase the expression of tumor/metastatic suppressors TPM1 & CADM1/2?

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References:

Web: http://genomediscovery.org or http://newbioideas.com/

Citation: Boominathan, L., Treating advanced cancers resistant to Paclitaxel/Topotecan/TemozolomideProbiotic-based Chemotherapy (PCT) targeting cancer stem cells and immune-inhibitory receptors in advanced ovarian cancer and in other advanced metastatic cancers resistant to Paclitaxel/Topotecan/Temozolomide: A pharmaceutical mixture encompassing Veliparib (ABT-888) and probiotic Lactobacillus rhamnosus increases the expression of tumor suppressor genes, such as TPM1, CADM1/2,  p53, and TA-p73/p63, INK4a and others, decreases PP2A expression, inhibits immune-inhibitory receptors/molecules, targets cancer stem cells, confers protection against chemoresistance mediated by Paclitaxel/Topotecan/Temozolomide, and stalls advanced ovarian cancers  progression, and prolongs survival, via up-regulation of its target gene, 7/November/2019, 11.59 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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